Rationale: Cystic fibrosis (CF; OMIM 219700) is a  common hereditary disease caused by mutations in the CFTR gene (OMIM 602421). The distribution and frequencies of the CFTR gene mutations vary considerably between countries and ethnic groups. By now about 11%  alleles of the CFTR gene remain unidentified after testing for frequent mutations in the Russian patients. A full determination of the mutation spectrum in the CFTR gene is necessary to optimize medical and genetic assistance to the population and to implement the achievements of targeted therapy in the treatment of CF patients.Materials and methods: The sample included 121 Russian CF patients, in whom testing for 34 routinely analyzed mutations did not identify one (n = 107) or both (n = 14) mutant alleles. Assessment of the coding sequence of the CFTR gene, including the regions of exon-intron junctions, 5’- and 3’-untranslated regions was performed by the Sanger sequencing method; in addition, the search for large rearrangements was conducted by the multiplex ligation-dependent probe amplification (MLPA) method.Results: In addition to the previously identified, 88  more variants were determined, including 28  missense mutations, 15  nonsense mutations, 18 frameshift mutations (14 deletions, 4  insertions), 14  splicing mutations, 1  in-frame insertion, 1  in-frame deletion, 1  in/del mutation, and 10  large rearrangements (7  deletions, 3  duplications). Twenty three (23) novel variants were sequenced. Four (4) complex mutant alleles were found. Sixty (60) variants are found once each. One hundred and thirty four (134) of 135 tested mutant alleles were identified.Conclusion: Consequent use of the sequencing and MLPA methods has allowed for identification of a high proportion of the tested mutant alleles in CF patients from Russia (134/135, > 99%), to detect a  significant diversity of the CFTR mutation spectrum (88  additional variants, 32  of them novel), a  number of repeated mutations (c.2353C>T, c.1240_1244delCAAAA, c.1766+1G>A and c.3929G>A) encountered in 5 or more unrelated patients, which could be included in the panel of routinely analyzed variants in the Russian CF patients; and a high proportion of large rearrangements of the CFTR gene.

Муковисцидоз (МВ) - аутосомно-рецессивное заболевание, обусловленное нарушением функции эпителиального хлорного канала, кодируемого геном CFTR. Спектр и частота вариантов последовательности гена CFTR, как и частота МВ различаются в разных странах и этнических группах. Изучено распределение частот вариантов гена CFTR у больных МВ и у здоровых индивидов в Республике Северной Осетия-Алания. Спектр патогенных вариантов у осетинских больных МВ отличается своеобразием: наиболее частыми являются два варианта W1282X (50%) и F508del (20%), тогда как в общероссийской выборке пациентов самыми частыми являются варианты F508del (52,8%) и CFTRdele2,3 (6,2%), а вариант W1282X (1,90%) относительно редок. В выборке здоровых осетин частоты выявленных вариантов W1282X и F508del составляют 0,0032 и 0,0016, соответственно. Cystic fibrosis (CF) is an autosomal recessive disease caused by impaired function of the epithelial chloride channel encoded by the CFTR gene. The spectrum and frequency of CFTR gene variants, as well as the CF incidence, vary in different countries and ethnic groups. The frequency distribution of CFTR gene variants in CF patients and in healthy individuals in the Republic of North Ossetia-Alania was studied. The spectrum of pathogenic variants in Ossetian CF patients is specific: the most frequent are two variants W1282X (50%) and F508del (20%), while in the all-Russian CF patients the most frequent are variants - F508del (52.8%) and CFTRdele2.3 (6.2%), and the variant W1282X (1.90%) is relatively rare. In healthy Ossetians, the frequencies of detected variants W1282X and F508del are 0.0032 and 0.0016, respectively. The most common CFTR gene variants are W1282X and F508del, found both in CF patients and healthy individuals from the Ossetian population of the Republic of North Ossetia-Alania.

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