Evaluation of the frequency of MEFV gene variants in patients with a pre-diagnosis of Familial Mediterranean Fever (FMF) in southeast Türkiye

Yıl 2023, Cilt: 16 Sayı: 3, 456 - 464, 01.07.2023

Derya Karaer Bahtiyar Şahinoğlu Abdullah İhsan Gürler Kadri Karaer

https://doi.org/10.31362/patd.1255344

Öz

Purpose: Familial Mediterranean Fever (FMF) is a hereditary auto inflammatory disease (MIM#249100). The most common symptoms are abdominal pain, high fever, and arthralgia. FMF is the result of variants in the MEditerraneanFeVer (MEFV) gene located on chromosome 16p13.3, which contains 10 exons and encodes the pyrin (marenostrin) protein. The frequency of MEFV gene variants that cause FMF varies according to ethnic groups, countries and even different regions in the same country. In our study, we aimed to determine the frequency and distribution of MEFV gene changes that cause Familial Mediterranean fever in southeast Türkiye.
Materials and methods: A total of 6.660 patients with a pre-diagnosis of FMF, including 3.495 women and 3.165 men, were included in the study. Fragment analysis was performed to investigate the MEFV gene variants of the patients and the 19 most common variants in the Turkish population were examined.
Results: We found at least one variant in 50.17% (3.341) of our 6.660 patients. In our patients, 108 different genotypes; in Exon 2, 3, 5 and 10 and we identified 16 different variants. We found 2.120 (63.21%) patients were heterozygous, 693 (20.74%) were compound heterozygotes, 275 (8.23%) were homozygous and 261 (7.81%) were complex genotypes. The five variants with the highest allele frequency are; R202Q (27.84%), M694V (22.83%), E148Q (21.98%), V726A (7.42%), and M680I (G>C) (6.39%).
Conclusion: We identified the most common prevalence of MEFV gene alteration in a large patient group in our region. High R202Q mutation rates were among the remarkable results of this study.

Anahtar Kelimeler

FMF, MEFV gene variations, fragment analysis

Türkiye'nin güneydoğusunda Ailevi Akdeniz Ateşi (AAA) ön tanısı alan hastalardaki MEFV gen varyantlarının sıklığının değerlendirilmesi

Öz

Amaç: Ailevi Akdeniz Ateşi (AAA) kalıtsal bir otoinflamatuar hastalıktır (MIM#249100). En sık görülen semptomlar yüksek ateş, karın ağrısı ve artraljidir. AAA, 16p13.3 kromozomu üzerinde yer alan, 10 ekzondan oluşan ve pirin (marenostrin) proteinini kodlayan MEditerraneanFeVer (MEFV) genindeki varyantların sonucudur. AAA'ya neden olan MEFV gen varyantlarının sıklığı etnik gruplara, ülkelere ve hatta aynı ülke içindeki farklı bölgelere göre değişmektedir. Bu çalışmada, Türkiye'nin güneydoğusunda Ailesel Akdeniz ateşine neden olan MEFV gen değişikliklerinin sıklığını ve dağılımını belirlemeyi amaçladık.
Gereç ve yöntem: Çalışmaya Ailevi Akdeniz Ateşi ön tanısı almış olan 3,495 kadın ve 3,165 erkek olmak üzere toplam 6.660 hasta dahil edildi. Hastaların MEFV gen varyantlarını araştırmak için fragman analizi yapıldı ve Türk popülasyonunda en sık görülen 19 varyant incelendi.
Bulgular: Çalışmaya dahil edilen 6,660 hastamızın %50,17'sinde (3,341) en az bir varyant tespit edildi. Hastalarımızda 108 farklı genotip; Exon 2, 3, 5 ve 10'da olmak üzere 16 farklı varyant belirledik. Hastaların 2,120’sinde (%63,21) heterozigot, 693’ünde (%20,74) bileşik heterozigot, 275’inde (%8,23) homozigot ve 261’inde (%7,81) kompleks genotip bulundu. Alel frekansı en yüksek olan 5 varyant sırasıyla; R202Q (%27,84), M694V (%22,83), E148Q (%21,98), V726A (%7,42) ve M680I (G>C) (%6,39) olarak belirlendi.
Sonuç: Bölgemizde geniş bir hasta grubunda yaptığımız bu çalışma ile FMF ön tanısı almış olan hastalarda en sık görülen MEFV gen değişikliklerinin sıklığını ve dağılımını belirledik. Yüksek R202Q mutasyon oranları bu çalışmanın dikkat çekici sonuçları arasında yer almaktadır.

Anahtar Kelimeler

FMF, MEFV gen varyasyonları, fragman analizi

Kaynakça

• 1. Sohar E, Gafni J, PrasM Heller J. Familial Mediterranean fever: a survey of 470 cases and review of the literature. Am J Med 1967;43:227-253. https://doi.org/10.1016/0002-9343(67)90167-2
• 2. Akyol ÖE, Ertan P. Familial MediterraneanfFever. Review. CBU-SBED 2020;7:413-417. http://doi.org/10.34087/cbusbed.696594
• 3. Fragouli E, Eliopoulos E, Petraki E, et al. Familial Mediterranean fever in crete: a genetic and structural biologicalapproach in a population of “intermediate risk”. Clin. Genet 2007;73:152-159. https://doi.org/10.1111/j.1399-0004.2007.00948.x
• 4. Akar N, Misiroğlu M, Yalcinkaya F, et al. MEFV mutations in Turkish patients suffering from Familial Mediterranean fever. Hum Mut 2000;15:118-119. https://doi.org/10.1002/(sici)1098-1004(200001)15:1%3C118::aid-humu29%3E3.0.co;2-5
• 5. Alghamdi M. Familial Mediterranean fever, review of the literature. Clin Rheumatol 2017;36:1707-1713. https://doi.org/10.1007/s10067-017-3715-5
• 6. Soriano A, Manna R. Familial Mediterranean fever: new phenotypes. Autoimmun Rev 2012;12:31-37. https://doi.org/10.1016/j.autrev. 2012.07.019
• 7. Tunca M, Akar S, Onen F, et al. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. Medicine (Baltimore) 2005;84:1-11. https://doi.org/10.1097/01.md.0000152370.84628.0c
• 8. FMF French Consortium. A candidate gene for Familial Mediterranean fever. Nat Genet 1997;17:25-31. https://doi.org/10.1038/ng0997-25
• 9. FMF International Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause Familial Mediterranean fever. Cell 1997;90:797-807. https://doi.org/10.1016/s0092-8674(00)80539-5
• 10. Infevers: an online database for autoinflammatory mutations. Copyright. Available at https://infevers.umai-montpellier.fr/web/. Accessed September 01, 2022
• 11. Dundar M, Emirogullari EF, Kiraz A, Taheri S, Baskol M. Common Familial Mediterranean fever gene mutations in a Turkish cohort. Mol Biol Rep 2011;38:5065-5069. https://doi.org/10.1007/s11033-010-0652-7
• 12. Dode C, Pecheux C, Cazeneuve C, et al. Mutations in the MEFV gene in a large series of patients with a clinical diagnosis of Familial Mediterranean fever. Am J Med Genet 2000;92:241-246. https://doi.org/10.1002/(SICI)1096-8628(20000605)92:4%3C241::AID-AJMG3%3E3.0.CO;2-G
• 13. Eisenberg S, Aksentijevich I, Deng Z, Kastner DL, Matzner Y. Diagnosis of Familial Mediterranean fever by a molecular genetics method. Ann Intern Med 1998;129:539-542. https://doi.org/10.7326/0003-4819-129-7-199810010-00005
• 14. Ozdogan H, Ugurlu S. Familial Mediterranean fever. Presse Med. 2019;48:61-76. https://doi.org/10.1016/j.lpm.2018.08.014
• 15. San A. Familial Mediterranean fever cases in Turkey. Int J Nephrol Kidney Fail 2020;6:1-8. http://dx.doi.org/10.16966/2380-5498.200
• 16. Yılmaz E, Ozen S, Balci B, et al. Mutation frequency of familial Mediterranean fever and evidence for a high carrier rate in the Turkish population. Eur J Hum Genet 2001;9:553-555. https://doi.org/10.1038/sj.ejhg.5200674
• 17. Ozen S, Batu ED. The myths we believed in Familial Mediterranean fever: what have we learned in the past years? Semin Immunopathol 2015;37:363-369. https://doi. org/10.1007/s00281-015-0484-6 18. Shohat M. Familial Mediterranean fever. University of Washington, Seattle.1993
• 19. Cekin N, Akyurek ME, Pinarbasi E, Ozen F. MEFV mutations and their relation to major clinical symptoms of Familial Mediterranean fever. Gene 2017;626:9-13. https://doi.org/10.1016/j.gene.2017.05.013
• 20. Coskun S, Ustyol L, Bayram Y, et al. The spectrum of MEFV gene mutations and genotypes in Van province, the eastern region of Turkey, and report of a novel mutation (R361T). Gene 2015;562:128-131. https://doi.org/10.1016/j.gene.2015.02.059
• 21. Jarjour RA, Al berrawi S. Familial Mediterranean fever in Syrian children: phenotype–genotype correlation. Rheumatol Int 2015;35:629-634. https://doi.org/10.1007/s00296-014-3116-x
• 22. Milenković J, Vojinović J, Debeljak M, et al. Distribution of MEFV gene mutations and R202Q polymorphism in the Serbian population and their influence on oxidative stress and clinical manifestations of inflammation. Pediatr Rheumatol 2016;14:1-9. https://doi.org/10.1186/s12969-016-0097-1
• 23. Yigit S, Karakus N, Tasliyurt T, et al. Significance of MEFV gene R202Q polymorphism in Turkish Familial Mediterranean fever patients. Gene 2012;506:43-45. https://doi.org/10.1016/j.gene.2012.06.074
• 24. Etem E. Familial Mediterranean fever: a retrospective clinical and molecular study in the East of Anatolia region of Turkey. Open Rheumatol J 2010;4:1-6. http://dx.doi.org/10.2174/1874312901004010001
• 25. Dundar M, Fahrioglu U, Yildiz SH, et al. Clinical and molecular evaluation of MEFV gene variants in the Turkish population: a study by the National Genetics Consortium. Funct Integr Genomics 2022;22:291-315. https://doi.org/10.1007/s10142-021-00819-3
• 26. Eyal O, Shinar Y, Pras M, Pras E. Familial Mediterranean fever: penetrance of the p.[Met694Val];[Glu148Gln] and p.[Met694Val];[=] genotypes. Hum Mutat 2020;41:1866-1870. https://doi.org/10.1002/humu. 24090
• 27. Aydın E, Cakmak E, Uluca U, et al. The MEFV mutations and their clinical correlations in children with Familial Mediterranean fever in southeast Turkey. Rheumatol Int 2014;34:207-212. http://dx.doi.org/10.1007/s00296-013-2858-1
• 28. Oztuzcu S, Ulaslı M, Ergun S, et al. Screening of common and novel Familial Mediterranean fever mutations in south-east part of Turkey. Mol Biol Rep 2014;41:2601-2607 http://dx.doi.org/10.1007/s11033-014-3118-5
• 29. Gumus E. The Frequency of MEFV gene mutations and genotypes in Sanliurfa province, south-eastern region of Turkey, after the Syrian civil war by using next generation sequencing and report of a novel exon 4 mutation (I423T). J Clin Med 2018;7:105-111 https://doi.org/10.3390/jcm7050105