Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients

Nika V Petrova,Anna Y Voronkova,Varvara A Galkina,Tatyana A Vasilyeva,Andrey V Marakhonov,Nataliya Y Kashirskaya,Elena K Zhekaite,Eugeny K Ginter,Victoria D Sherman,Sergey I Kutsev,Elena I Kondratyeva,Rena A Zinchenko

doi:10.3390/genes11050554

Abstract

The distribution and frequency of the CFTR gene mutations vary considerably between countries and ethnic groups. Russians are an East Slavic ethnic groups are native to Eastern Europe. Russians, the most numerous people of the Russian Federation (RF), make about 80% of the population. The aim is to reveal the molecular causes of CF in ethnic Russian patients as comprehensively as possible. The analysis of most common CFTR mutations utilized for CF diagnosis in multiethnic RF population accounts for about 83% of all CF-causing mutations in 1384 ethnic Russian patients. Variants c.1521_1523delCTT (F508del), c.54-5940_273+10250del21kb (CFTRdele2,3), c.2012delT (2143delT), c.2052_2053insA (2184insA), and c.3691delT (3821delT) are most typical for CF patients of Russian origin. DNA of 154 CF patients, Russian by origin, in whom at least one mutant allele was not previously identified (164 CF alleles), was analyzed by Sanger sequencing followed by the multiplex ligase-dependent probe amplification (MLPA) method. In addition to the 29 variants identified during the previous test for common mutations, 91 pathogenic CFTR variants were also revealed: 29 missense, 19 nonsense, 14 frame shift in/del, 17 splicing, 1 in frame ins, and 11 copy number variations (CNV). Each of the 61 variants was revealed once, and 17 twice. Each of the variants c.1209G>C (E403D), c.2128A>T (K710X), c.3883delA (4015delA), and c.3884_3885insT (4016insT) were detected for three, c.1766+1G>A (1898+1G>A) and c.2834C>T (S945L) for four, c.1766+1G>C (1898+1G>C) and c.(743+1_744-1)_(1584+1_1585-1)dup (CFTRdup6b-10) for five, c.2353C>T (R785X) and c.4004T>C (L1335P) for six, c.3929G>A (W1310X) for seven, c.580-1G>T (712-1G>T for eight, and c.1240_1244delCAAAA (1365del5) for 11 unrelated patients. A comprehensive analysis of CFTR mutant alleles with sequencing followed by MLPA, allowed not only the identification of 163 of 164 unknown alleles in our patient sample, but also expansion of the mutation spectrum with novel and additional frequent variants for ethnic Russians.

Highlights

Cystic fibrosis (CF, OMIM#219700) is an autosomal recessive condition resulting from the pathogenic variants in the CF transmembrane regulator (CFTR) gene
The panel includes 33 pathogenic variants of the CFTR gene identified in patients from different regions of the Russian Federation, as well as the variants specific for certain ethnic groups [7,8,9,10], and allows identification of up to 85% of mutant alleles in all-Russian population [12]
CFTRdele2,3, eight more variants can be referred to as frequent ones for ethnic Russians

Summary

Introduction

Cystic fibrosis (CF, OMIM#219700) is an autosomal recessive condition resulting from the pathogenic variants in the CF transmembrane regulator (CFTR) gene. CF is a hereditary disease caused by impaired epithelial chloride channel CFTR function. Variants are classified as disease causing, not disease causing, of variable clinical significance, or of unknown clinical significance. More than different variants of the CFTR gene sequence have been revealed, the pathogenicity of 20% of. In many populations the most frequent pathogenic variant of the CFTR gene (ABCC7) is F508del, which accounts for approximately two thirds of all CFTR alleles, with a decreasing prevalence from Northwest to Southeast Europe. The remaining third of alleles are substantially heterogeneous, with fewer than 20 mutations occurring at a worldwide frequency of more than 0.1%

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Discussion

Conclusion