Abstract

Background. The aim of this study was to investigate whether a short exon screening consisting of selected variants could confirm the diagnosis in patients with a preliminary diagnosis of familial Mediterranean fever (FMF), thus providing a cost-saving alternative to a comprehensive MEditerranean FeVer (MEFV) gene sequence analysis test.

Methods. This observational study on pediatric patients focused on clinically suspected FMF cases without prior genetic analysis. Participants met the Turkish pediatric FMF criteria. They underwent short exon screening for M694V, M680I, V726A, and E148Q variants. Those who were heterozygous or negative on short exon screening received further MEFV gene sequence analysis.

Results. The study involved 1557 patients. Pathogenic variants in both alleles of the MEFV gene were found in 611 patients (39.2%), and a high-penetrance variant in heterozygosity or an E148Q variant on the other allele was found in 643 patients (41.3%). A further 189 patients (12.1%) had one or two E148Q variants. Short-exon screening was negative in 114 patients (7.6%). Of the 876 patients who underwent MEFV gene sequence analysis, additional variants were found in 72 of the 762 initially heterozygous patients. Of the 114 initially negative patients, 34 had homozygous or compound heterozygous variants, and 74 had heterozygous variants. Ultimately, only 6 patients yielded negative results in the MEFV gene sequence analysis.

Conclusion. The short exon screening for common MEFV mutations offers a practical and cost-saving alternative to comprehensive MEFV gene sequence analysis in populations with a high prevalence of FMF.

Keywords: Familial Mediterranean fever, genetics, diagnosis, cost-saving

How to cite

1.
Sözeri B, Çağlayan Ş, Coşkuner T, Kendir-Demirkol Y. Cost-saving approach with screening of selected variants in genetic diagnosis in Turkish pediatric familial Mediterranean fever patients: a single center longitudinal study. Turk J Pediatr 2024; 66: 465-472. https://doi.org/10.24953/turkjpediatr.2024.4580

References

  1. Ben-Chetrit E, Touitou I. Familial Mediterranean fever in the world. Arthritis Rheum 2009; 61: 1447-1453. https://doi.org/10.1002/art.24458
  2. Ozalkaya E, Mir S, Sozeri B, Berdeli A, Mutlubas F, Cura A. Familial Mediterranean fever gene mutation frequencies and genotype-phenotype correlations in the Aegean region of Turkey. Rheumatol Int 2011; 31: 779-784. https://doi.org/10.1007/s00296-010-1383-8
  3. Ozen S, Karaaslan Y, Ozdemir O, et al. Prevalence of juvenile chronic arthritis and familial Mediterranean fever in Turkey: a field study. J Rheumatol 1998; 25: 2445-2449.
  4. Yalçinkaya F, Ozen S, Ozçakar ZB, et al. A new set of criteria for the diagnosis of familial Mediterranean fever in childhood. Rheumatology (Oxford) 2009; 48: 395-398. https://doi.org/10.1093/rheumatology/ken509
  5. Sohar E, Gafni G, Pras M. Tel Hashomer criteria for the diagnosis of FMF. In: Sohar E, Gafni G, Pras M, editors. Proceedings of the First International Conference on FMF. London and Tel Aviv: Freund Publishing House; 1997: 207.
  6. Livneh A, Langevitz P, Zemer D, et al. Criteria for the diagnosis of familial Mediterranean fever. Arthritis Rheum 1997; 40: 1879-1885. https://doi.org/10.1002/art.1780401023
  7. Sag E, Demirel D, Demir S, et al. Performance of the new 'Eurofever/PRINTO classification criteria' in FMF patients. Semin Arthritis Rheum 2020; 50: 172-175. https://doi.org/10.1016/j.semarthrit.2019.08.004
  8. Stoffels M, Szperl A, Simon A, et al. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann Rheum Dis 2014; 73: 455-461. https://doi.org/10.1136/annrheumdis-2012-202580
  9. The International FMF 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. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997; 17: 25-31. https://doi.org/10.1038/ng0997-25
  11. Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015; 17: 405-424. https://doi.org/10.1038/gim.2015.30
  12. Van Gijn ME, Ceccherini I, Shinar Y, et al. New workflow for classification of genetic variants' pathogenicity applied to hereditary recurrent fevers by the International Study Group for Systemic Autoinflammatory Diseases (INSAID). J Med Genet 2018; 55: 530-537. https://doi.org/10.1136/jmedgenet-2017-105216
  13. Ben-Chetrit E, Urieli-Shoval S, Calko S, Abeliovich D, Matzner Y. Molecular diagnosis of FMF: lessons from a study of 446 unrelated individuals. Clin Exp Rheumatol 2002; 20: S25-S29.
  14. Tufan A, Lachmann HJ. Familial Mediterranean fever, from pathogenesis to treatment: a contemporary review. Turk J Med Sci 2020; 50: 1591-1610. https://doi.org/10.3906/sag-2008-11
  15. Öztürk K, Coşkuner T, Baglan E, et al. Real-life data from the largest pediatric familial Mediterranean fever cohort. Front Pediatr 2022; 9: 805919. https://doi.org/10.3389/fped.2021.805919
  16. Booth DR, Gillmore JD, Lachmann HJ, et al. The genetic basis of autosomal dominant familial Mediterranean fever. QJM 2000; 93: 217-221. https://doi.org/10.1093/qjmed/93.4.217
  17. Booty MG, Chae JJ, Masters SL, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum 2009; 60: 1851-1861. https://doi.org/10.1002/art.24569
  18. Touitou I. The spectrum of familial Mediterranean fever (FMF) mutations. Eur J Hum Genet 2001; 9: 473-483. https://doi.org/10.1038/sj.ejhg.5200658
  19. Yaşar Bilge Ş, Sarı İ, Solmaz D, et al. The distribution of MEFV mutations in Turkish FMF patients: multicenter study representing results of Anatolia. Turk J Med Sci 2019; 49: 472-477. https://doi.org/10.3906/sag-1809-100
  20. Dundar M, Kiraz A, Emirogullari EF, et al. A molecular analysis of familial Mediterranean fever disease in a cohort of Turkish patients. Ann Saudi Med 2012; 32: 343-348. https://doi.org/10.5144/0256-4947.2012.343
  21. Kırnaz B, Gezgin Y, Berdeli A. MEFV gene allele frequency and genotype distribution in 3230 patients' analyses by next generation sequencing methods. Gene 2022; 827: 146447. https://doi.org/10.1016/j.gene.2022.146447
  22. Kilim Y, Magal N, Shohat M. Expanding the panel of MEFV mutations for routine testing of patients with a clinical diagnosis of familial Mediterranean fever. Isr Med Assoc J 2011; 13: 206-208.
  23. Moradian MM, Sarkisian T, Ajrapetyan H, Avanesian N. Genotype-phenotype studies in a large cohort of Armenian patients with familial Mediterranean fever suggest clinical disease with heterozygous MEFV mutations. J Hum Genet 2010; 55: 389-393. https://doi.org/10.1038/jhg.2010.52
  24. Mattit H, Joma M, Al-Cheikh S, et al. Familial Mediterranean fever in the Syrian population: gene mutation frequencies, carrier rates and phenotype-genotype correlation. Eur J Med Genet 2006; 49: 481-486. https://doi.org/10.1016/j.ejmg.2006.03.002
  25. Koç İ. Türkiye'de akraba evliliklerinin yaygınlığının değişimi ve dirençli grupların belirlenmesi: 2018 Türkiye Nüfus ve Sağlık Araştırması'ndan evlilik kuşaklarına göre analizler. Turkish Journal of Public Health 2022; 20: 423-438. https://doi.org/10.20518/tjph.1114922
  26. Rowczenio DM, Youngstein T, Trojer H, et al. British kindred with dominant FMF associated with high incidence of AA amyloidosis caused by novel MEFV variant, and a review of the literature. Rheumatology (Oxford) 2020; 59: 554-558. https://doi.org/10.1093/rheumatology/kez334