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CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.

Ziętkiewicz E, Rutkiewicz E, Pogorzelski A, Klimek B, Voelkel K, Witt M - PLoS ONE (2014)

Bottom Line: 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).Most of the mutations repetitively found in Polish patients had been previously described in other European populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.

ABSTRACT
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.

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CFTR mutation detection efficiency in PL CF patients from different health centers.A. Both mutations identified. B. One mutation identified. C. No mutation identified. Diagonal stripes – INNOLiPA mutations; solid black – non-INNOLiPA mutations. Rabka – Institute of Tuberculosis and Lung Diseases in Rabka; Other – other health care centers in Poland.
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pone-0089094-g001: CFTR mutation detection efficiency in PL CF patients from different health centers.A. Both mutations identified. B. One mutation identified. C. No mutation identified. Diagonal stripes – INNOLiPA mutations; solid black – non-INNOLiPA mutations. Rabka – Institute of Tuberculosis and Lung Diseases in Rabka; Other – other health care centers in Poland.

Mentions: To illustrate potential impact of the care center on the correct clinical diagnosis and thus on the efficiency of mutation detection, we compared the results obtained for two subgroups of our cohort (Fig. 1): patients from the national CF reference center (Institute of Tuberculosis and Lung Diseases in Rabka; N = 368) and from other health centers (general pediatric hospitals in Poznan and other cities, excluding Warsaw (see below); N = 370). The success of the IL tests (detection of both mutations) was 79% in Rabka and 58% in other centers (p<0.0001; Pearson’s chi square test). After the extended gene screening, the number of patients with no mutations detected remained significantly (p<0.0001) higher in patients from the general pediatric centers (∼23%) than in patients from the specialized CF center in Rabka (∼5%). The observed discrepancy can be interpreted as indicating the lower rate of a successful clinical CF diagnosis outside the reference center. Of note, among the patients from Rabka with only one or with no mutation found, ∼80% had high sweat chloride values; in the corresponding group from the peripheral centers, high chloride values were reported only in ∼50% of the patients, while the other half had ambiguous chloride values or no test results had been reported.


CFTR mutations spectrum and the efficiency of molecular diagnostics in Polish cystic fibrosis patients.

Ziętkiewicz E, Rutkiewicz E, Pogorzelski A, Klimek B, Voelkel K, Witt M - PLoS ONE (2014)

CFTR mutation detection efficiency in PL CF patients from different health centers.A. Both mutations identified. B. One mutation identified. C. No mutation identified. Diagonal stripes – INNOLiPA mutations; solid black – non-INNOLiPA mutations. Rabka – Institute of Tuberculosis and Lung Diseases in Rabka; Other – other health care centers in Poland.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3935850&req=5

pone-0089094-g001: CFTR mutation detection efficiency in PL CF patients from different health centers.A. Both mutations identified. B. One mutation identified. C. No mutation identified. Diagonal stripes – INNOLiPA mutations; solid black – non-INNOLiPA mutations. Rabka – Institute of Tuberculosis and Lung Diseases in Rabka; Other – other health care centers in Poland.
Mentions: To illustrate potential impact of the care center on the correct clinical diagnosis and thus on the efficiency of mutation detection, we compared the results obtained for two subgroups of our cohort (Fig. 1): patients from the national CF reference center (Institute of Tuberculosis and Lung Diseases in Rabka; N = 368) and from other health centers (general pediatric hospitals in Poznan and other cities, excluding Warsaw (see below); N = 370). The success of the IL tests (detection of both mutations) was 79% in Rabka and 58% in other centers (p<0.0001; Pearson’s chi square test). After the extended gene screening, the number of patients with no mutations detected remained significantly (p<0.0001) higher in patients from the general pediatric centers (∼23%) than in patients from the specialized CF center in Rabka (∼5%). The observed discrepancy can be interpreted as indicating the lower rate of a successful clinical CF diagnosis outside the reference center. Of note, among the patients from Rabka with only one or with no mutation found, ∼80% had high sweat chloride values; in the corresponding group from the peripheral centers, high chloride values were reported only in ∼50% of the patients, while the other half had ambiguous chloride values or no test results had been reported.

Bottom Line: 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).Most of the mutations repetitively found in Polish patients had been previously described in other European populations.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Clinical Genetics, Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus