Ailevi Akdeniz Ateşi Hastalarında MEFV Geninin NGS ile Analizi: Tek Merkez Deneyimi

Amaç: Ailevi Akdeniz ateşi (FMF) Akdeniz ülkelerinde sıklıkla görülen, otoinflamatuar bir multisistem hastalıktır. MEFV geni, bu hastalıktan sorumlu tutulmuştur. Bu çalışmada FMF ön tanısı olan hastaların MEFV geninin araştırılması amaçlanmıştır. Materyal ve Metod: Bu retrospektif kohort çalışması 01.06.2018 – 01.07.2020 tarihleri arasında, Ankara Dışkapı Yıldırım Beyazıt Eğitim ve Araştırma Hastanesi, Tıbbi Genetik Bölümü’nde gerçekleşti. Çalışmada, FMF ön tanılı 220 hastanın Yeni Nesil Dizileme yöntemi ile araştırılmış olan MEFV genine ait bulguları değerlendirilmiştir. Bulgular: Çalışmadaki 220 hastanın (142 kadın, 78 erkek) yaş ortalaması 35,6±11,4 idi. Hastaların 131’nde (%0,59) MEFV geninde varyant tespit edildi. Allel sayıları ve frekansları değerlendirildiğinde en sık tespit edilen varyantlar sırasıyla M694V, V726A, M680I ve E148Q olarak belirlendi. Bu varyantların 152’si heterozigot, 20’si homozigot, 36’sı bileşik heterozigot ve 3’ü kompleks genotip durumundaydı. Sonuç: Çalışmamızın sonucunda elde edilen bulgular, Türkiye’den FMF hasta gruplarında daha önce bildirilen veriler ile uyumludur. Bu çalışma, Türkiye MEFV gen spektrumu verilerine katkı sağlayacaktır.

Anahtar Kelimeler:

Ailevi Akdeniz ateşi, FMF, MEFV, M694V, E148Q

Analysis of the MEFV Gene by NGS in Patients with Familial Mediterranean Fever: A Single Center Experience

Background: Familial Mediterranean fever (FMF) is an autoinflammatory multisystemic disease common seen in Mediterranean countries. The MEFV gene has been implicated in the disease. In this study, it was aimed to investigate the MEFV gene of patients with a pre-diagnosis of FMF by using NGS method.Materials and Methods: This retrospective study was held between 01.06.2018 - 01.07.2020 in Ankara Dışkapı Yıldırım Beyazıt Training and Research Hospital, Department of Medical Genetics. In this study, the findings of the MEFV gene of 220 patients with a pre-diagnosis of FMF, which were investigated by Next Generation Sequencing method, were evaluated. Results: The mean age of 220 patients (142 women, 78 men) in the study was 35.6 ± 11.4 years. Variant was detected in the MEFV gene in 131 (59%) of the patients. When allele numbers and frequencies were evaluated, the most frequently detected variants were M694V, V726A, M680I and E148Q, respectively. Of these variants, 152 were heterozygous, 20 were homozygous, 36 were compound heterozygous, and 3 were complex genotypes.Conclusion: The findings obtained in this study are consistent with data reported previously in patients with FMF group from Turkey. The performed NGS analysis made it possible to detect rare variants as well as the MEFV gene variants frequently observed in FMF patients. This work will contribute to the FMF gene Turkey spectral data.

Keywords:

Familial Mediterranean Fever, FMF, MEFV, M694V, E148Q,

PDF

___

1. Ozen S, Karaaslan Y, Ozdemir O, Saatci U, Bakkaloglu A, Koroglu E, et al. Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. The Journal of rheumatology. 1998;25(12):2445-9.
2. Yalçınkaya F, Group TFS. Familial Mediterranean fever (FMF) in Turkey: results of a nationwide multicenter study. 2005.
3. Twig G, Livneh A, Vivante A, Afek A, Shamiss A, Derazne E, et al. Mortality risk factors associated with familial Mediterranean fever among a cohort of 1.25 million adolescents. Annals of the rheumatic diseases. 2014;73(4):704-9.
4. Kasifoglu T, Bilge SY, Sari I, Solmaz D, Senel S, Emmungil H, et al. Amyloidosis and its related factors in Turkish patients with familial Mediterranean fever: a multicentre study. Rheumatology. 2014;53(4):741-5.
5. Booty MG, Chae JJ, Masters SL, Remmers EF, Barham B, Le JM, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2009;60(6):1851-61.
6. Marek‐Yagel D, Berkun Y, Padeh S, Abu A, Reznik‐Wolf H, Livneh A, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis & Rheumatism: Official Journal of the American College of Rheumatology. 2009;60(6):1862-6.
7. Masters SL, Lagou V, Jéru I, Baker PJ, Van Eyck L, Parry DA, et al. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Science translational medicine. 2016;8(332):332ra45-ra45.
8. Mankan A, Kubarenko A, Hornung V. Immunology in clinic review series; focus on autoinflammatory diseases: inflammasomes: mechanisms of activation. Clinical & Experimental Immunology. 2012;167(3):369-81.
9. Berkun Y, Padeh S, Reichman B, Zaks N, Rabinovich E, Lidar M, et al., editors. A single testing of serum amyloid a levels as a tool for diagnosis and treatment dilemmas in familial Mediterranean fever. Seminars in arthritis and rheumatism; 2007: Elsevier.
10. Goulielmos G, Fragouli E, Aksentijevich I, Sidiropoulos P, Boumpas D, Eliopoulos E. Mutational analysis of the PRYSPRY domain of pyrin and implications for familial mediterranean fever (FMF). Biochemical and biophysical research communications. 2006;345(4):1326-32.
11. Ben‐Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Care & Research. 2009;61(10):1447-53.
12. Giancane G, Ter Haar NM, Wulffraat N, Vastert SJ, Barron K, Hentgen V, et al. Evidence-based recommendations for genetic diagnosis of familial Mediterranean fever. Annals of the Rheumatic Diseases. 2015;74(4):635-41.
13. Kocakap DBS, Günel-Özcan A, Cabuk F, Ensari C. The frequency of Familial Mediterranean fever gene mutations and genotypes at Kirikkale and comparison with the mean of regional MEFV mutation frequency of Turkey. Molecular biology reports. 2014;41(3):1419-26.
14. Rowczenio DM, Iancu DS, Trojer H, Gilbertson JA, Gillmore JD, Wechalekar AD, et al. Autosomal dominant familial Mediterranean fever in Northern European Caucasians associated with deletion of p. M694 residue—a case series and genetic exploration. Rheumatology. 2017;56(2):209-13.
15. Bonyadi M, Esmaeili M, Jalali H, Somi M, Ghaffari A, Rafeey M, et al. MEFV mutations in Iranian Azeri Turkish patients with familial Mediterranean fever. Clinical genetics. 2009;76(5):477-80.
16. Stoffels M, Szperl A, Simon A, Netea MG, Plantinga TS, van Deuren M, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Annals of the Rheumatic Diseases. 2014;73(2):455-61. 17. Hentgen V, Grateau G, Stankovic‐Stojanovic K, Amselem S, Jéru I. Familial Mediterranean fever in heterozygotes: are we able to accurately diagnose the disease in very young children? Arthritis & Rheumatism. 2013;65(6):1654-62.
18. Lachmann H, Şengül B, Yavuzşen T, Booth D, Booth S, Bybee A, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology. 2006;45(6):746-50.
19. Kalyoncu M, Acar BC, Cakar N, Bakkaloglu A, Ozturk S, Dereli E, et al. Are carriers for MEFV mutations" healthy"? Clinical and experimental rheumatology. 2006;24(5 Suppl 42):S120-2.
20. Federici S, Calcagno G, Finetti M, Gallizzi R, Meini A, Vitale A, et al. Clinical impact of MEFV mutations in children with periodic fever in a prevalent western European Caucasian population. Annals of the rheumatic diseases. 2012;71(12):1961-5.
21. Ozturk C, Halıcıoglu O, Coker I, Gulez N, Sutçuoglu S, Karaca N, et al. Association of clinical and genetical features in FMF with focus on MEFV strip assay sensitivity in 452 children from western Anatolia, Turkey. Clinical rheumatology. 2012;31(3):493-501.
22. Marek-Yagel D, Bar-Joseph I, Pras E, Berkun Y. Is E148Q a benign polymorphism or a disease-causing mutation? The Journal of rheumatology. 2009;36(10):2372-.
23. Shinar Y, Obici L, Aksentijevich I, Bennetts B, Austrup F, Ceccherini I, et al. Guidelines for the genetic diagnosis of hereditary recurrent fevers. Annals of the rheumatic diseases. 2012;71(10):1599-605.
24. Ben‐Chetrit E, Lerer I, Malamud E, Domingo C, Abeliovich D. The E148Q mutation in the MEFV gene: is it a disease‐causing mutation or a sequence variant? Human mutation. 2000;15(4):385-6.
25. Touitou I, Lesage S, McDermott M, Cuisset L, Hoffman H, Dode C, et al. Infevers: an evolving mutation database for auto‐inflammatory syndromes. Human mutation. 2004;24(3):194-8.
26. Gershoni-Baruch R, Brik R, Shinawi M, Livneh A. The differential contribution of MEFV mutant alleles to the clinical profile of familial Mediterranean fever. European Journal of Human Genetics. 2002;10(2):145-9.
27. Majeed HA, El-Khateeb M, El-Shanti H, Rabaiha ZA, Tayeh M, Najib D, editors. The spectrum of familial Mediterranean fever gene mutations in Arabs: report of a large series. Seminars in arthritis and rheumatism; 2005: Elsevier.