Epidemiological Evaluation of Next-Generation Sequencing and MLPA Results in Patients with a Presumptive Cystic Fibrosis Diagnosis

Year 2024, Volume: 46 Issue: 5, 747 - 758, 12.09.2024

Sezin Canbek , Murat Hakkı Yarar , Metin Eser , Hakan Yazan

https://doi.org/10.20515/otd.1482361

Abstract

Cystic fibrosis is an autosomal recessive disease caused by pathogenic variants in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The spectrum and frequencies of CFTR mutations vary among populations. As a result of continuous migration around the world, the frequency of CF variants may change and is still unclear in some geographies. We aimed to define the CFTR gene variants we observed as a result of our single-center experience. This research assessed the outcomes of 353 patients who underwent next-generation sequencing to identify variations in the CFTR gene. Variants classified as clinically uncertain significance, likely pathogenic or pathogenic detected in patients with pre-diagnosis of cystic fibrosis who underwent genetic testing were included in the evaluation. The variants detected in the vast majority of cases were comparable to those found in other populations. However, some variants showed significant differences in allele frequencies when compared to European and Asian populations. Mutations were detected in 25.2% of cases. This dataset revealed that the most common mutations in patients presenting to our center were c.2991G>C, c.2856G>C, c.1545_1546delTA, c.1521_1523 del and c.202A>G. This research presents data on CFTR variations to determine the frequency of CF in the Istanbul province of our nation and to identify additional frequently occurring pathogenic variants that are currently unknown. This kind of research has the potential to facilitate the creation of a localized strategy for maximizing healthcare provision for individuals with CF.

Keywords

CFTR, Cystic Fibrozis, Next Generation Sequencing, Retrospective

Project Number

00181514775

Kistik Fibrozis Ön Tanılı Hastaların Yeni Nesil Dizileme ve MLPA Sonuçlarının Epidemiyolojik Değerlendirilmesi

Abstract

Kistik fibröz, kistik fibroz transmembran iletkenlik düzenleyici (CFTR) genindeki patojenik varyantların neden olduğu otozomal resesif bir hastalıktır. CFTR mutasyonlarının spektrumu ve frekansları popülasyonlar arasında farklılık gösterir. Dünyada sürekli gerçekleşen göçler neticesinde KF varyantlarının görülme sıklığı değişebilmekte ve bazı coğrafyalarda hala netlik göstermemektedir. Tek merkez deneyimimiz neticesinde gözlemlediğimiz CFTR geni varyantlarını tanımlamayı amaçladık. Bu çalışmada, CFTR genindeki varyantların yeni nesil dizileme yöntemi ile araştırıldığı 353 hastanın sonuçları değerlendirilmiştir. Kistik fibroz ön tanısı almış ve genetik test yaptırmış hastalarda klinik olarak belirsiz öneme sahip, muhtemelen patojenik veya patojenik olarak sınıflandırılan varyantlar değerlendirmeye dahil edildi. Vakaların büyük çoğunluğunda tespit edilen varyantlar diğer popülasyonlarda bulunan varyantlarla karşılaştırılabilirdi. Ancak bazı varyantlar Avrupa ve Asya popülasyonlarıyla karşılaştırıldığında alel frekanslarında önemli farklılıklar gösterdi. Mutasyonlar vakaların %25,2'sinde tespit edildi. Bu veri seti, merkezimize başvuran hastalarda en sık görülen mutasyonların c.2991G>C, c.2856G>C, c.1545_1546delTA, c.1521_1523 del ve c.202A>G olduğunu ortaya koydu. Bu çalışma, ülkemiz İstanbul ili KF prevalansını tahmin etmek ve bilinmeyen ancak sık görülen diğer patojenik varyantları ortaya çıkarmak için CFTR varyantları hakkında bilgi sağlamaktadır. Bunun gibi çalışmalar, KF hastalarının tıbbi bakımını optimize etmek için bölgesel bir yaklaşımın geliştirilmesine yardımcı olabilecektir.

Keywords

CFTR, Kistik Fibrozis, Yeni Nesil Dizileme, Retrospektif

Ethical Statement

SBÜ Ümraniye EAH Etik Kurulu Onayı alınmıştır.

Supporting Institution

-

Project Number

00181514775

Thanks

Hastalarımıza teşekkürlerimizle.

References

• 1. Koster IM, Loomis CA, Koss T, et al. Skin Development and Maintenance. Dermatology. Ed. Bolognia JL, Jorizzo Jl, Schafer JV. 3. Elsevier, 2012;55-64.
• 2. Morasso IM, Chu DH, Schwarz T: Structure and function of the skin. Pediatric Dermatology. Ed. Schachner LA, Ronald CH. 4th Edition. Mosby, 2011:1-50
• 3. Christoph T, Müller-Röver S, Audring H, et al. The human hair follicle immune system: cellular composition and immune privilege. Br J Dermatol. 2000;142:862-73.
• 4. Dogan S, Atakan N. Immunology of the hair follicle. Turkderm-Archives of the Turkish Dermatology and Venerology. 2014; 48:10-2
• 5. Shin JM, Son S, Jung KE, et al. Possible role of β-hydroxybutyrate in inducing inflammation in alopecia areata. Exp Dermatol. 2024;33(6):15117.
• 6. Huang KP, Mullangi S, Guo Y, et al. Autoimmune, Atopic, and Mental Health Comorbid Conditions Associated with Alopecia Areata in the United States. JAMA Dermatol 2013;149:789-94
• 7. Sutic Udovic I, Hlaca N, Massari LP, et al. Deciphering the Complex Immunopathogenesis of Alopecia Areata. Int J Mol Sci. 2024;25(11):5652.
• 8. Ortiz-Ramirez A, Hernandez-Jimenez MC, Guardiola-Avila IB, et al. HR Gene Variants Identified in Mexican Patients with Alopecia Areata. Curr Issues Mol Biol. 2023;45(4):2965-2971.
• 9. Juarez-Rendon KJ, Rivera Sanchez G, Reyes-Lopez MA, et al. Alopecia Areata. Current situation and perspectives. Alopecia Areata. Current situation and perspectives. Arch Argent Pediatr. 2017;115(6):e404-e411.
• 10. Yoshimasu T, Furukawa F. Modified immunotherapy for alopecia areata. Autoimmun Rev. 2016;15(7):664-667.
• 11. Wolff H, Fischer TW, Blume-Peytavi U. The Diagnosis and Treatment of Hair and Scalp Diseases. Dtsch Arztebl Int. 2016;113(21):377-386.
• 12. Shehata WA, Maraee A, Kamal H, et al. Protein tyrosine phosphatase nonreceptor type 22 gene polymorphism in alopecia areata: Does it have an association with disease severity?. J Cosmet Dermatol. 2020;19(11):3138-3144. 13. Kalkan G, Karakus N, Bas Y, et al. The association between Interleukin (IL)-4 gene intron 3 VNTR polymorphism and alopecia areata (AA) in Turkish population. Gene. 2013;527(2):565-569.
• 14. Abdel Ghany SM, Sayed AA, El-Deek SEM, et al. Obesity risk prediction among women of Upper Egypt: The impact of serum vaspin and vaspin rs2236242 gene polymorphism. Gene. 2017;626:140-148.
• 15. Yamawaki H. Vascular effects of novel adipocytokines: Focus on vascular contractility and inflammatory responses. Biological and Pharmaceutical Bulletin. 2011;34(3):307-310.
• 16. Dizen Namdar N, Akcilar R, Bayat Z. Association between Vaspin rs2236242 Gene Polymorphism and Psoriasis Vulgaris. Skin Pharmacol Physiol. 2020;33(6):317-322.
• 17. Saalbach A, Tremel J, Herbert D, et al. Anti-Inflammatory Action of Keratinocyte-Derived Vaspin: Relevance for the Pathogenesis of Psoriasis. Am J Pathol. 2016;186(3):639-651.
• 18. Hosseini M, Nezhadali M, Hedayati M. Association of vaspin rs2236242 gene polymorphism with serum vaspin level, insulin resistance and diabetes in an Iranian diabetic/pre-diabetic population. J Med Biochem. 2021;40(1):33-40.
• 19. Radzicka S, Pietryga M, Iciek R, et al. The role of visfatin in pathogenesis of gestational diabetes (GDM). Ginekol Pol. 2018;89(9):518-521.
• 20. Javanmard SH, Dehghananzadeh R, Rafiee L, et al. Genetic associations of the visfatin G-948T polymorphism with obesity-related metabolic traits in an Iranian population. J Res Med Sci. 2016;21:105.
• 21. Marjani S, Nezhadali M, Hekmat A, et al. Investigating Visfatin gene Polymorphism rs4730153 with Insulin Resistance and Non-Alcoholic Fatty Liver Diseases in Iranian Population. Iran J Public Health. 2022;51(5):1143-1151.
• 22. Suliga E, Koziel D, Ciesla E, et al. Associations Between Vaspin Rs2236242 Gene Polymorphism, Walking Time and the Risk of Metabolic Syndrome. Balkan J Med Genet. 2019;22(1):41-48.
• 23. Oran FK, Gheybi A, Celik F et al. Investigation of Gene Polymorphisms of Vaspin, Visfatin and Chemerin Obese and Non-Diabetic Obese Patients. Journal of Health Services and Education 2021;5(2):33-38.
• 24. Papi A, Nezhadali M, Alinezhad M. Relationship of serum visfatin level in obese individuals with insulin and body mass index. Journal of Police Medicine. 2018;7(4):161-165.
• 25. Khorrami-Nezhad L, Mirzaei K, Maghbooli Z, et al. Dietary fat intake associated with bone mineral density among visfatin genotype in obese people. Br J Nutr. 2018;119(1):3-11.
• 26. Chang SL, Yang PJ, Lin YY, et al. Genetic Associations of Visfatin Polymorphisms with EGFR Status and Clinicopathologic Characteristics in Lung Adenocarcinoma. Int J Environ Res Public Health. 2022;19(22):15172.
• 27. Chen KJ, Hsieh MH, Lin YY, et al. Visfatin Polymorphisms, Lifestyle Risk Factors and Risk of Oral Squamous Cell Carcinoma in a Cohort of Taiwanese Males. Int J Med Sci. 2022;19(4):762-768.
• 28. Jianjun L, Xiaona L, Hong L. The effect of visfatin genotype on insulin pump therapy on quality of life in patients with type I diabetes. Cell Mol Biol (Noisy-le-grand). 2022;67(4):195-202.
• 29. Tilg H, Moschen AR. Adipocytokines: Mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6:772-783.
• 30. Guzik TJ, Mangalat D, Korbut R (2006 Adipocytokines - novel link between inflammation and vascular function?. Journal of physiology and pharmacology: an official journal of the Polish Physiological Society. 2006;57(4), 505–528.
• 31. Incel Uysal P, Akdogan N, Alli N, et al. Assessment of Metabolic Profile and Ischemia-modified Albumin Level in Patients with Alopecia Areata: A Case-Control Study. Indian J Dermatol. 2019;64(1):12-18.
• 32. Ismail SA, Mohamed SA. Serum levels of visfatin and omentin-1 in patients with psoriasis and their relation to disease severity. Br J Dermatol. 2012;167(2):436-439.
• 33. Coban M, Tasli L, Turgut S, et al. Association of Adipokines, Insulin Resistance, Hypertension and Dyslipidemia in Patients with Psoriasis Vulgaris. Ann Dermatol. 2016;28(1):74-79.
• 34. Wu Y, Hui Y, Liu F, et al. The Association of Serum Adipokines, Insulin Resistance and Vitamin D Status in Male Patients with Androgenetic Alopecia. Clin Cosmet Investig Dermatol. 2023;16:419-427.