Dataset Information

Molecular Analysis of Cystic Fibrosis Patients in Hungary - An Update to the Mutational Spectrum.

ABSTRACT: BACKGROUND:In this study the authors present an update to the CFTR mutation profile in Hungary, utilizing data from a selected cohort of 45 cystic fibrosis (CF) patients from different regions of the country. METHODS:Depending on the preceding analysis, four different mutation detection methods were used. A commercial assay targeting the most common CF-causing mutations was performed as the first test followed by an allele specific PCR for CFTRdele2,3(21kb), Sanger sequencing and MLPA analysis of the coding region of the CFTR gene. RESULTS:In our recent study 27 different mutations were detected, including 2 novel ones (c.1037_1038insA and c.1394C>T). Besides F508del (c.1521_1523delCTT), the following mutations were found at a frequency of ? 4.0%: W1282X (c.3846G>A), N1303K (c.3909C>G), CFTRdele2,3(21kb) (c.54-5940_273+10250del21kb) and 2184insA (c.2052_2053insA). In addition, four mutations (G542X, Y1092X, 621+1G>T, and 2143delT) were found in more than one allele. CONCLUSIONS:The updated database of Hungarian mutations not only enables to increase the efficiency of the existing diagnostic approach, but also provides a further refined basis for the introduction of the molecular newborn screening (NBS) program in Hungary.

SUBMITTER: Ivady G

PROVIDER: S-EPMC4922332 | biostudies-literature | 2015 Jan

REPOSITORIES: biostudies-literature

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Molecular Analysis of Cystic Fibrosis Patients in Hungary - An Update to the Mutational Spectrum.

Ivády Gergely G Koczok Katalin K Madar Laszlo L Gombos Eva E Toth Izabella I Gyori Klaudia K Balogh István I

Journal of medical biochemistry 20141008 1

<h4>Background</h4>In this study the authors present an update to the <i>CFTR</i> mutation profile in Hungary, utilizing data from a selected cohort of 45 cystic fibrosis (CF) patients from different regions of the country.<h4>Methods</h4>Depending on the preceding analysis, four different mutation detection methods were used. A commercial assay targeting the most common CF-causing mutations was performed as the first test followed by an allele specific PCR for CFTRdele2,3(21kb), Sanger sequenci ...[more]

PMID: 28356823

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Project description: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.

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

Molecular Analysis of Cystic Fibrosis Patients in Hungary - An Update to the Mutational Spectrum.

Publications

Molecular Analysis of Cystic Fibrosis Patients in Hungary - An Update to the Mutational Spectrum.

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