EVALUATİON OF GENETİC TESTİNG İN ADULT PATİENTS WİTH SUSPECTED SYSTEMİC AUTOİNFLAMMATORY DİSORDERS

Öz

Objective: This study aimed to compare the clinical features of patients with suspected systemic autoinflammatory diseases (SAIDs) by genetic status to identify the characteristics of variant-negative patients.

Materials and Methods: Clinical findings and results of the targeted next-generation sequencing of “fever panel genes” of patients with suspected SAIDs were retrospectively reviewed using their medical records.

Results: Records of 137 patients (79 females, 58 males, mean age 40.8±12.6) referred to our clinic between April 2019 and January 2023 were evaluated. Variants associated with the relevant phenotypes were identified in 105 patients (76.6%), whereas 32 (23.4%) had no pathogenic or likely pathogenic variants, nor variants of uncertain significance (VUS). Variant-negative patients were older at diagnosis than variant-positive ones (38.2±13.6 vs. 28.4±14.8 years; p=0.02). Fever and arthritis occurred with a similar frequency between the groups. Compared with the variant-positive patients, the variant-negative group more often presented with nausea, weight loss, diarrhoea, erythema nodosum, headache, and sensorineural hearing loss (SNHL). Cerebrovascular occlusion occurred more frequently among variant-positive patients.

Conclusion: Our study illustrates that the yield of genetic screening is expected to be low in patients older than 40 years and those presenting with nausea, weight loss, diarrhoea, erythema nodosum, headache, and SNHL. A better definition of those variant-negative patients may identify some subgroups of patients with SAID features associated with potential multifactorial causes or somatic mosaic variants.

Anahtar Kelimeler

• Systemic autoinflammatory diseases
• genetic screening
• genetic variant
• variant-negative patients

SİSTEMİK OTOİNFLAMATUAR HASTALIK ŞÜPHESİ OLAN ERİŞKİN HASTALARDA GENETİK TESTLERİN DEĞERLENDİRİLMESİ

Öz

Amaç: Bu çalışma, sistemik otoinflamatuvar hastalık (SOIH) şüphesi olan hastaların klinik özelliklerini genetik durumlarına göre karşılaştırarak varyant-negatif hastaların özelliklerini belirlemeyi amaçlamıştır.

Gereç ve Yöntemler: SOIH şüphesiyle yollanan hastaların klinik bulguları ve ateş paneli genetik tarama sonuçları dosyalarındaki kayıtlardan retros-pektif olarak değerlendirildi.

Bulgular: Kliniğimize Nisan 2019 ve Ocak 2023 tarihleri arasında başvuran toplam 137 hastanın (79 kadın, 58 erkek, ortalama yaş 40,8±12,6) verisi değerlendirildi. İlgili fenotiplerle ilişkili varyantlar 105 hastada (%76,6) saptanırken, 32 hastada (%23,4) patojenik, olası patojenik veya anlamı belirsiz varyant (VUS) tespit edilmedi. Varyant-negatif hastalar, varyant-pozitif hastalara kıyasla tanı anında daha ileri yaştaydı (38,2±13,6 yıla karşı 28,4±14,8; p=0,02). Ateş ve artrit her iki grupta benzer sıklıkta görüldü. Varyant-negatif grupta bulantı, kilo kaybı, ishal, eritema nodozum, baş ağrısı ve sensörinöral işitme kaybı (SNIK) daha sık izlendi. Serebrovasküler oklüzyon ise varyant-pozitif hastalarda daha sık görüldü.

Sonuç: Bu araştırma, 40 yaşının üstünde ve bulantı, kilo kaybı, ishal, eritema nodozum, başağrısı ve SNIK bulguları olan hastalarda genetik taramada sonuç elde etme oranının düşük olduğunu göstermektedir. Varyant saptanmayan hastaların özelliklerinin daha iyi tanımlanması sonucu multifaktöriyel ya da somatik mozaisizmle ilişkili SOIH alt grup-larının saptanması mümkün olabilir.

Anahtar Kelimeler

• Sistemik otoinflamatuar hastalıklar
• genetik tarama
• genetik varyant
• varyant negatif hastalar

Kaynakça

1. Van Gijn ME, Ceccherini I, Shinar Y, Carbo EC, Slofstra M, Arostegui JI, et al. New workflow for the 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(8):530-7. google scholar
2. Chen X, Yu X. Cohort-driven variant burden analysis and pathogenicity identification in monogenic autoinflammatory disorders. J Allergy Clin Immunol 2023;152(2):517-27. google scholar
3. Gattorno M, Hofer M, Federici S, Vanoni F, Bovis F, Aksentijevich I et al. Classification criteria for autoinflammatory recurrent fevers. Ann Rheum Dis 2019;78(8):1025-32. google scholar
4. Cantarini L, Vitale A, Lucherini OM, De Clemente C, Caso F, Costa L et al. The labyrinth of autoinflammatory disorders: a snapshot of the activity of a third-level centre in Italy. Clin Rheumatol 2015;34:17-28. google scholar
5. Papa R, Penco F, Volpi S, Sutera D, Caorsi R, Gattorno M. Syndrome of undifferentiated recurrent fever: an emerging group of autoinflammatory recurrent fevers. J Clin Med 2021;10(9):1963. google scholar
6. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J 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(5):405-23. google scholar
7. Amikishiyev S, Kalayci T, Deniz R, Soltanova L, Yalçinkaya Y, Artim-Esen B, et al. POS0367 Phenotypes of patients with more than one autoinflammatory gene variant: classified diseases and mixed autoinflammatory disorders (MAID). Ann Rheum Dis 2024;83(Suppl 1):356-7. google scholar
8. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol 2009;27(1):621-68. google scholar

9. de Jesus AA, Canna SW, Liu Y, Goldbach-Mansky R. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signalling. Annu Rev Immunol 2015;33(1):823-74. google scholar
10. Thomas KT, Feder Jr HM, Lawton AR, Edwards KM. Periodic fever syndrome in children. J Pediatr 1999;135(1):15-21. google scholar
11. Ben-Chetrit E, Levy M. Familial Mediterranean fever. Lancet 1998;351(9103):659-64. google scholar
12. Ter Haar NM, Jeyaratnam J, Lachmann HJ, Simon A, Brogan PA, Doglio M et al. The phenotype and genotype of mevalonate kinase deficiency: a series of 114 cases from the Eurofever registry. Arthritis Rheumatol 2016;68(11):2795-805. google scholar
13. van der Hilst JC, Bodar EJ, Barron KS, Frenkel J, Drenth JP, van der Meer JW, et al. Longterm follow-up, clinical features, and quality of life in a series of 103 patients with hyperimmunoglobulinemia D syndrome. Medicine (Baltimore) 2008;87(6):301-10. google scholar
14. Bader-Meunier B, Florkin B, Sibilia J, Acquaviva C, Hachulla E, Grateau G et al. Mevalonate kinase deficiency: a survey of 50 patients. Paediatrics 2011;128(1):e152-e9. google scholar
15. Cantarini L, Lucherini OM, Brucato A, Barone L, Cumetti D, Iacoponi F et al. Clues to detect tumour necrosis factor receptor-associated periodic syndrome (TRAPS) among patients with idiopathic recurrent acute pericarditis: results of a multicentre study. Clin Res Cardiol 2012;101:525-31. google scholar
16. Deuitch N, Laird R, Matthiasardottir B, Wang H, Rosensweig S, Pimpale P et al. eP340: Clinical and genetic features of a large cohort of individuals with autoinflammatory disease. Genetics in Medicine 2022;24(3):S212-S3. google scholar
17. Rama M, Mura T, Kone-Paut I, Boursier G, Aouinti S, Touitou I et al. Is gene panel sequencing more efficient than clinical-based gene sequencing to diagnose autoinflammatory diseases? A randomised study. Clin Exp Immunol 2021;203(1):105-14. google scholar
18. Niewold TB, Aksentijevich I, Gorevic PD, Gibson G, Yao Q. Genetically transitional disease: conceptual understanding and applicability to rheumatic disease. Nat Rev Rheumatol 2024;20(5):301-10. google scholar
19. Stewart OJ, Gruber C, Randolph HE, Patel R, Ramba M, Calzoni E et al. Monoallelic expression can govern the penetrance of inborn errors of immunity. Nature 2025:1-12. google scholar
20. Rowczenio DM, Gomes SM, Aróstegui JI, Mensa-Vilaro A, Omoyinmi E, Trojer H, et al. Late-onset cryopyrin-associated periodic syndromes caused by somatic NLRP3 mosaicism —UK single centre experience. Front Immunol 2017;8:1410. google scholar
21. Ionescu D, Peñín‐Franch A, Mensa‐Vilaró A, Castillo P, Hurtado‐Navarro L, Molina‐López C et al. First description of late‐onset autoinflammatory disease due to somatic NLRC4 mosaicism. Arthritis Rheumatol 2022;74(4):692-9. google scholar
22. Kontzias A, Zarabi SK, Calabrese C, Wang Y, Judis L, Yao Q et al. Somatic mosaicism in adult‐onset TNF receptor‐associated periodic syndrome (TRAPS). Mol Genet Genomic Med 2019;7(8):e791. google scholar
23. Beck DB, Ferrada MA, Sikora KA, Ombrello AK, Collins JC, Pei W et al. Somatic mutations in UBA1 and severe adult-onset autoinflammatory disease. N Engl J Med 2020;383(27):2628-38. google scholar