Analysis of CFTR mutation spectrum in Yugra region (Russian Federation)

Rapid progress in both molecular diagnostics tools and targeted therapy for cystic fibrosis (CF) requires clear understanding of CFTR mutation spectrum in population constantly living in any large region of any country. There are still no published results of comprehensive genetic study of CF patients from the Yugra region (Western Siberian part of Russia). Three-step molecular genetic approach was used for gDNA samples derived from a group of 54 CF patients living in the Yugra region: (1) AFLP/RFLP was used for the panel of 35 major CFTR mutations; (2) NGS, for full sequencing of exons and exon-intron boundaries of CFTR gene; and (3) the MLPA technique, to search for large gene rearrangements. The search of major CFTR mutations in multiethnic Yugra population accounted for only 76.6 % of all CF-causing mutations. Most common were variants F508del (rs113993960), 1677delTA (rs121908776), CFTRdele2,3, E92K (rs121908751), R1066C (rs78194216). Genomic DNA samples from 19 CF patients from the tested group in which only one mutant allele was identified were analyzed by the NGS approach followed by MLPA. This allowed to reveal 19 rare pathogenic CFTR variants, including five new variants absent in CF mutation databases. Generally, three-tier molecular genetics approach applied for the first time for a Yugra-originated cohort of CF patients allowed to find 12 missense mutations, 9 nonsense ones, 6 in/dels, 4 splice-site variants, 1 CNV. Three alleles remained unidentified. Deciphering the genetic background for CF patients living in Yugra allowed to support rational administration of CFTR modulators with profound clinical effect. The need to develop a region-specific testing panel for common CFTR mutations is demonstrated.

1. Amaral M.D., Pankonien I. Cystic fibrosis as a paradigmatic disease in bringing science to the bedside. FEBS Lett. 2025;599(22):31963207. doi 10.1002/1873-3468.70101

2. Ayupova G., Litvinov S., Akhmetova V., Minniakhmetov I., Mokrysheva N., Khusainova R. Population characteristics of the spectrum and frequencies of CFTR gene mutations in patients with cystic fibrosis from the Republic of Bashkortostan (Russia). Genes (Basel). 2024;15(10):1335. doi 10.3390/genes15101335

3. Bobadilla J.L., Macek M., Jr., Fine J.P., Farrell P.M. Cystic fibrosis: a worldwide analysis of CFTR mutations – correlation with incidence data and application to screening. Hum Mutat. 2002;19(6):575-606. doi 10.1002/humu.10041

4. Callebaut I., Chong P.A., Forman-Kay J.D. CFTR structure. J Cyst Fibros. 2018;17(2S):S5-S8. doi 10.1016/j.jcf.2017.08.008

5. Castellani C., Simmonds N.J., Barben J., Addy C., Bevan A., Burgel P.R., Drevinek P., … Nährlich L., Raraigh K., Sermet-Gaudelus I., Sommerburg O., Southern K.W. Standards for the care of people with cystic fibrosis (CF): a timely and accurate diagnosis. J Cyst Fibros. 2023;22(6):963-968. doi 10.1016/j.jcf.2023.09.008

6. Dörk T., Macek M., Mekus F., Tümmler B., Tzountzouris J., Casals T., Krebsová A., … Stuhrmann M., Bauer I., Seydewitz H.H., Neumann T., Jakubiczka S. Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe. Hum Genet. 2000;106(3):259-268. doi 10.1007/s004390000246

7. Farrell P.M., White T.B., Howenstine M.S., Munck A., Parad R.B., Rosenfeld M., Sommerburg O., … Wilschanski M., Sermet-Gaudelus I., Blau H., Gartner S., McColley S.A. Diagnosis of cystic fibrosis in screened populations. J Pediatr. 2017;181S:S33-S44.e2. doi 10.1016/j.jpeds.2016.09.065

8. Ivaschenko T., Bakay M., Baranov V. Novel frameshift mutation in exon 4 of CFTR gene. Hum Mutat. 1995;5(2):184-185. doi 10.1002/ humu.1380050215

9. Kondratyeva E.I., Kashirskaya N.Y., Kapranov N.I. (Eds) National Consensus Project. Cystic Fibrosis: Definition, Diagnostic Criteria, Treatment. Moscow, 2019 (in Russian)

10. Ong T., Ramsey B.W. Cystic fibrosis: a review. JAMA. 2023;329(21): 1859-1871. doi 10.1001/jama.2023.8120

11. Parisi G.F., Terlizzi V., Manti S., Papale M., Pecora G., Presti S., Tosto M., Leonardi S. Cutting-edge advances in cystic fibrosis: from gene therapy to personalized medicine and holistic management. Genes (Basel). 2025;16(4):402. doi 10.3390/genes16040402

12. Petrova N.V., Kondratyeva E.I., Krasovsky S.A., Polyakov A.V., Ivachshenko T.E., Pavlov A.E., Zinchenko R.A., … Semykin S.Y., Sergienko D.F., Simonova O.I., Shabalova L.A., Kashirskaya N.Y. National Consensus Project “Cystic fibrosis: definition, diagnostic criteria, treatment” Section “Genetics of Cystic Fibrosis. Molecular genetic diagnosis of cystic fibrosis”. Med Genet. 2016;15(11):29-45 (in Russian)

13. Petrova N.V., Kashirskaya N.Y., Vasilyeva T.A., Kondratyeva E.I., Zhekaite E.K., Voronkova A.Y., Sherman V.D., Galkina V.A., Ginter E.K., Kutsev S.I., Marakhonov A.V., Zinchenko R.A. Analysis of CFTR mutation spectrum in ethnic Russian cystic fibrosis patients. Genes (Basel). 2020;11(5):554. doi 10.3390/genes11050554

14. Petrova N., Balinova N., Marakhonov A., Vasilyeva T., Kashirskaya N., Galkina V., Ginter E., Kutsev S., Zinchenko R. Ethnic differences in the frequency of CFTR gene mutations in populations of the European and North Caucasian part of the Russian Federation. Front Genet. 2021;12:678374. doi 10.3389/fgene.2021.678374 Registry of Patients with Cystic Fibrosis in the Russian Federation. 2023. Moscow, 2025. doi 10.61726/1981.2025.26.16.001 (in Russian)

15. Sosnay P.R., Salinas D.B., White T.B., Ren C.L., Farrell P.M., Raraigh K.S., Girodon E., Castellani C. Applying cystic fibrosis transmembrane conductance regulator genetics and CFTR2 data to fa-

16. Conflict of interest. The authors declare no conflict of interest.

17. cilitate diagnoses. J Pediatr. 2017a;181S:S27-S32.e1. doi 10.1016/ j.jpeds.2016.09.063

18. Sosnay P.R., White T.B., Farrell P.M., Ren C.L., Derichs N., Howenstine M.S., Nick J.A., De Boeck K. Diagnosis of cystic fibrosis in nonscreened populations. J Pediatr. 2017b;181S:S52-S57.e2. doi 10.1016/j.jpeds.2016.09.068

19. Stepanova A.A., Abrukova A.V., Savaskina E.N., Poliakov A.V. Mutation p.E92K is the primary cause of cystic fibrosis in Chuvashes. Russ J Genet. 2012;48:731-737. doi 10.1134/S102279541

20.

21. Stepanova A.A., Galeeva N.M., Schagina O.A., Ryzhkova O.P., Krasovsky S.A., Voronkova A.Y., Zhekaite E.K., Melyanovskaya Y.L., Kondratyeva E.I., Polyakov A.V. Results of the extended genotyping program for patients with suspected cystic fibrosis. Med Genet. 2025;24(7):100-103. doi 10.25557/2073-7998.2025.07.100-103 (in Russian)

22. Terlizzi V., Lopes-Pacheco M. Cystic fibrosis: new challenges and perspectives beyond elexacaftor/tezacaftor/ivacaftor. Ther Adv Respir Dis. 2025;19:17534666251323194. doi 10.1177/17534666

23.

24. Therrell B.L., Padilla C.D., Borrajo G.J.C., Khneisser I., Schielen P.C.J.I., Knight-Madden J., Malherbe H.L., Kase M. Current status of newborn bloodspot screening worldwide 2024: a comprehensive review of recent activities (2020–2023). Int J Neonatal Screen. 2024;10(2):38. doi 10.3390/ijns10020038

25. Zhang J., Yao Y., He H., Shen J. Clinical interpretation of sequence variants. Curr Protoc Hum Genet. 2020;106(1):e98. doi 10.1002/ cphg.98

26. Zolin A., Adamoli A., Bakkeheim E. ECFSPR Annual Report 2023. European Cystic Fibrosis Society, 2025. Available: https://www.ecfs. eu/sites/default/files/Annual%20Report_2023_vs1.2_ECFSPR_ 20250721.pdf