Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients

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.

Current Status of Genetic Diagnosis Laboratories and Frequency of Genetic Variants Associated with Cystic Fibrosis through a Newborn-Screening Program in Turkey

“…Even though the p.F508del mutation accounts for 70% of CF mutations in white patients of northern European descent, it has differing percentages in other populations [ 18 ]. In the Russian population, the p.F508del mutation accounts for 53% of mutations [ 19 ], and this is caused by the specific ethnic background of the population. Thus, screening for known CF gene mutations did not help to ameliorate such inequities in our population, but the combination of NGS with MLPA was more successful, as explained in the Results Section.…”

Targeted Sequencing of 242 Clinically Important Genes in the Russian Population From the Ivanovo Region

“…Moreover, this whole-exome study demonstrated the overrepresentation of several disease-causing variants for Mendelian disorders, such as phenylketonuria (PAH, rs5030858), Wilson's disease (ATP7B, rs76151636), factor VII deficiency (F7, rs36209567), and the kyphoscoliosis type of Ehlers-Danlos syndrome (FKBP14, rs542489955). For the Russian population, however, pathogenic variant frequencies were reported mostly for relatively small cohorts including patients and their families and targeted at specific genes and disorders, for example, familial hypercholesterolemia (Meshkov et al, 2021;Miroshnikova et al, 2021); cystic fibrosis, phenylketonuria, alpha-1 antitrypsin deficiency, and sensorineural hearing loss (Kiseleva et al, 2020;Petrova et al, 2020); cardiomyopathy (Marakhonov et al, 2019;Zaklyazminskaya et al, 2019;Kulikova et al, 2021;Shestak et al, 2021); and breast and ovarian cancer (Brovkina et al, 2018;Solodskikh et al, 2019).…”

Clinical Presentation of the c.3844T>C (p.Trp1282Arg, W1282R) Variant in Russian Cystic Fibrosis Patients

“…Variant c.3844T>C (p.Trp1282Arg, W1282R) is included in the panel of common mutations that are routinely tested in the Russian population as the first step of molecular analysis of CF [ 11 , 14 , 19 ]. Molecular genetic testing for the c.3844T>C (p.Trp1282Arg, W1282R) variant is performed by restriction analysis.…”

“…The second most common variant in Chuvash CF patients is F508del (30%) [ 10 ]. In regions with a predominantly Russian population, the most frequent are the F508del (49–65%) and CFTRdele2,3 (2–7%) variants [ 7 , 11 ]. A number of variants that are relatively frequent in Russian patients are not found in the other regions of the world [ 12 , 13 , 14 ], e.g., L138ins [ 11 , 15 ], W1282R [ 7 , 11 ], and 3272-16T>A [ 11 , 16 ].…”