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

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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. 

About the authors

N. V. Petrova

Medical Genetic Science Center

Author for correspondence.
Email: npetrova63@mail.ru

PhD, Doctor of Biol. Sci., Leading Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

A. Yu. Marakhonov

Medical Genetic Science Center

Email: fake@neicon.ru

PhD (in Biol.), Senior Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

T. A. Vasilyeva

Medical Genetic Science Center

Email: fake@neicon.ru

Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

N. Yu. Kashirskaya

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Professor, Chief Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

E. I. Kondratyeva

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Professor, Chief Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

E. K. Zhekayte

Medical Genetic Science Center

Email: fake@neicon.ru

MD, Research Fellow, Clinical and Consulting Department of Cystic Fibrosis,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

A. Yu. Voronkova

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Senior Research Fellow, Clinical and Consulting Department of Cystic Fibrosis,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

V. D. Sherman

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Senior Research Fellow, Clinical and Consulting Department of Cystic Fibrosis,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

V. A. Galkina

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Senior Research Fellow, Laboratory of Genetic Epidemiology,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

E. K. Ginter

Medical Genetic Science Center

Email: fake@neicon.ru

PhD, Doctor of Biol. Sci., Professor, Academician of the Russian Academy of Sciences, Scientific Head,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

S. I. Kutsev

Medical Genetic Science Center

Email: fake@neicon.ru

MD, PhD, Professor, Corresponding Member of the Russian Academy of Sciences, Director,

1 Moskvorech'e ul., Moscow, 115522

Russian Federation

R. A. Zinchenko

Medical Genetic Science Center;
Moscow Regional Research and Clinical Institute (MONIKI)

Email: fake@neicon.ru

MD, PhD, Professor, Head of Laboratory of Genetic Epidemiology, 1 Moskvorech'e ul., Moscow, 115522;

Professor of Clinical Pharmacology Course of the Chair of Organizational and Legal Support of Medical and Pharmaceutical Activities, Postgraduate Training Faculty, 61/2 Shchepkina ul., Moscow, 129110

Russian Federation

References

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Copyright (c) 2019 Petrova N.V., Marakhonov A.Y., Vasilyeva T.A., Kashirskaya N.Y., Kondratyeva E.I., Zhekayte E.K., Voronkova A.Y., Sherman V.D., Galkina V.A., Ginter E.K., Kutsev S.I., Zinchenko R.A.

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