Dataset Information

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.

SUBMITTER: Petrova NV

PROVIDER: S-EPMC7288340 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.

Petrova Nika V NV Kashirskaya Nataliya Y NY Vasilyeva Tatyana A TA Kondratyeva Elena I EI Zhekaite Elena K EK Voronkova Anna Y AY Sherman Victoria D VD Galkina Varvara A VA Ginter Eugeny K EK Kutsev Sergey I SI Marakhonov Andrey V AV Zinchenko Rena A RA

Genes 20200515 5

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 popula ...[more]

PMID: 32429104

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Project description:BackgroundIncreasing the activity of defective cystic fibrosis transmembrane conductance regulator (CFTR) protein is a potential treatment for cystic fibrosis.MethodsWe conducted a randomized, double-blind, placebo-controlled trial to evaluate ivacaftor (VX-770), a CFTR potentiator, in subjects 12 years of age or older with cystic fibrosis and at least one G551D-CFTR mutation. Subjects were randomly assigned to receive 150 mg of ivacaftor every 12 hours (84 subjects, of whom 83 received at least one dose) or placebo (83, of whom 78 received at least one dose) for 48 weeks. The primary end point was the estimated mean change from baseline through week 24 in the percent of predicted forced expiratory volume in 1 second (FEV(1)).ResultsThe change from baseline through week 24 in the percent of predicted FEV(1) was greater by 10.6 percentage points in the ivacaftor group than in the placebo group (P<0.001). Effects on pulmonary function were noted by 2 weeks, and a significant treatment effect was maintained through week 48. Subjects receiving ivacaftor were 55% less likely to have a pulmonary exacerbation than were patients receiving placebo, through week 48 (P<0.001). In addition, through week 48, subjects in the ivacaftor group scored 8.6 points higher than did subjects in the placebo group on the respiratory-symptoms domain of the Cystic Fibrosis Questionnaire-revised instrument (a 100-point scale, with higher numbers indicating a lower effect of symptoms on the patient's quality of life) (P<0.001). By 48 weeks, patients treated with ivacaftor had gained, on average, 2.7 kg more weight than had patients receiving placebo (P<0.001). The change from baseline through week 48 in the concentration of sweat chloride, a measure of CFTR activity, with ivacaftor as compared with placebo was -48.1 mmol per liter (P<0.001). The incidence of adverse events was similar with ivacaftor and placebo, with a lower proportion of serious adverse events with ivacaftor than with placebo (24% vs. 42%).ConclusionsIvacaftor was associated with improvements in lung function at 2 weeks that were sustained through 48 weeks. Substantial improvements were also observed in the risk of pulmonary exacerbations, patient-reported respiratory symptoms, weight, and concentration of sweat chloride. (Funded by Vertex Pharmaceuticals and others; VX08-770-102 ClinicalTrials.gov number, NCT00909532.).

Project description:Cystic fibrosis (CF) is the most common genetic disease among Caucasians, and accordingly the cystic fibrosis transmembrane conductance regulator (CFTR) protein has perhaps the best characterized disease mutation spectrum with more than 1,500 causative mutations having been identified. In this study, we took advantage of that wealth of mutational information in an effort to relate site-specific evolutionary parameters with the propensity and severity of CFTR disease-causing mutations. To do this, we devised a scoring scheme for known CFTR disease-causing mutations based on the Grantham amino acid chemical difference matrix. CFTR site-specific evolutionary constraint values were then computed for seven different evolutionary metrics across a range of increasing evolutionary depths. The CFTR mutational scores and the various site-specific evolutionary constraint values were compared in order to evaluate which evolutionary measures best reflect the disease-causing mutation spectrum. Site-specific evolutionary constraint values from the widely used comparative method PolyPhen2 show the best correlation with the CFTR mutation score spectrum, whereas more straightforward conservation based measures (ConSurf and ScoreCons) show the greatest ability to predict individual CFTR disease-causing mutations. While far greater than could be expected by chance alone, the fraction of the variability in mutation scores explained by the PolyPhen2 metric (3.6%), along with the best set of paired sensitivity (58%) and specificity (60%) values for the prediction of disease-causing residues, were marginal. These data indicate that evolutionary constraint levels are informative but far from determinant with respect to disease-causing mutations in CFTR. Nevertheless, this work shows that, when combined with additional lines of evidence, information on site-specific evolutionary conservation can and should be used to guide site-directed mutagenesis experiments by more narrowly defining the set of target residues, resulting in a potential savings of both time and money.

Project description:Cystic fibrosis (CF) is caused by mutations in the cystic fibrosis transmembrane regulator gene (CFTR). In light of the strong allelic heterogeneity and regional specificity of the mutation spectrum, the strategy of molecular diagnostics and counseling in CF requires genetic tests to reflect the frequency profile characteristic for a given population. The goal of the study was to provide an updated comprehensive estimation of the distribution of CFTR mutations in Polish CF patients and to assess the effectiveness of INNOLiPA_CFTR tests in Polish population. The analyzed cohort consisted of 738 patients with the clinically confirmed CF diagnosis, prescreened for molecular defects using INNOLiPA_CFTR panels from Innogenetics. A combined efficiency of INNOLiPA CFTR_19 and CFTR_17_TnUpdate tests was 75.5%; both mutations were detected in 68.2%, and one mutation in 14.8% of the affected individuals. The group composed of all the patients with only one or with no mutation detected (109 and 126 individuals, respectively) was analyzed further using a mutation screening approach, i.e. SSCP/HD (single strand conformational polymorphism/heteroduplex) analysis of PCR products followed by sequencing of the coding sequence. As a result, 53 more mutations were found in 97 patients. The overall efficiency of the CF allele detection was 82.5% (7.0% increase compared to INNOLiPA tests alone). The distribution of the most frequent mutations in Poland was assessed. Most of the mutations repetitively found in Polish patients had been previously described in other European populations. The most frequent mutated allele, F508del, represented 54.5% of Polish CF chromosomes. Another eight mutations had frequencies over 1%, 24 had frequencies between 1 and 0.1%; c.2052-2053insA and c.3468+2_3468+3insT were the most frequent non-INNOLiPA mutations. Mutation distribution described herein is also relevant to the Polish diaspora. Our study also demonstrates that the reported efficiency of mutation detection strongly depends on the diagnostic experience of referring health centers.

Dataset Information

Analysis of CFTR Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.

Publications

Analysis of <i>CFTR</i> Mutation Spectrum in Ethnic Russian Cystic Fibrosis Patients.

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