Characteristics of the mutation spectrum identified by comprehensive investigation of the  CFTR  gene in the Russian patients

N. V. Petrova; Петрова Н. В.; A. Yu. Marakhonov; Марахонов А. Ю.; T. A. Vasilyeva; Васильева Т. А.; N. Yu. Kashirskaya; Каширская Н. Ю.; E. I. Kondratyeva; Кондратьева Е. И.; E. K. Zhekayte; Жекайте Е. К.; A. Yu. Voronkova; Воронкова А. Ю.; V. D. Sherman; Шерман В. Д.; V. A. Galkina; Галкина В. А.; E. K. Ginter; Гинтер Е. К.; S. I. Kutsev; Куцев С. И.; R. A. Zinchenko; Зинченко Р. А.

doi:10.18786/2072-0505-2019-47-004

Characteristics of the mutation spectrum identified by comprehensive investigation of the CFTR gene in the Russian patients

Authors: Petrova N.V.¹, Marakhonov A.Y.¹, Vasilyeva T.A.¹, Kashirskaya N.Y.¹, Kondratyeva E.I.¹, Zhekayte E.K.¹, Voronkova A.Y.¹, Sherman V.D.¹, Galkina V.A.¹, Ginter E.K.¹, Kutsev S.I.¹, Zinchenko R.A.¹^,2
Affiliations:
1. Medical Genetic Science Center
2. Moscow Regional Research and Clinical Institute (MONIKI)
Issue: Vol 47, No 1 (2019)
Pages: 38-46
Section: ARTICLES
URL: https://almclinmed.ru/jour/article/view/967
DOI: https://doi.org/10.18786/2072-0505-2019-47-004
ID: 967

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Abstract

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.