CFTR Mutations Spectrum and the Efficiency of Molecular Diagnostics in Polish Cystic Fibrosis Patients

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.

A Clinical and Molecular Survey of 62 Cystic Fibrosis Patients from Umbria (Central Italy) Disclosing a High Frequency (2.4%) of the 2184insA Allele: Implications for Screening

“…It is localized in exon 14 of the CFTR gene in the polyA tract where, more commonly, at least in the Italian population, the deletion of 1 or 2 nucleotides determining the c.2052delA (2184delA) mutation is observed. In studies conducted in populations of Eastern European countries (Ukraine, Hungary, Poland, and Slovakia), the 2184insA mutation was reported as a severe mutation, an assumption that is in line also with our findings [15,16]. In fact, regardless of the second allele, all our patients showed PI; nevertheless, only 1 case was identified from the neonatal screening.…”

Comprehensive genetic study of cystic fibrosis in Slovak patients in 25 years of genetic diagnostics

“…As expected, the most common mutation was F508del which was detected in 60.36% of all patient chromosomes; and this approximately corresponds to the expected frequency considering Slovakia's location in Europe and the accepted geographic frequency gradient of this mutation. In addition to F508del, only 9 mutations were observed over 1% frequency, and these are common at similar frequency in the neighboring central European countries of The Czech Republic, Austria, Poland, Hungary and Ukraine; as previously described and discussed (Figure ).…”

“…Mutations with frequencies >1% in neighboring countries and lower/not detected in Slovakia are in bold. Mutations with frequency >1% in Slovakia and lower/not detected in neighboring countries are underlined…”

Uncommon clinical presentation of cystic fibrosis in a patient homozygous for a rare CFTR mutation: a case report

“…This mutation is sporadic, not found in the CFTR2 Database, but registered in the CFTR and HGMD Databases. Hitherto it has only been reported in patients of Polish origin and only in combination with other mutations [6]. The applied method (DNA sequencing) enables the detection of rare mutations and new changes, which are not registered in databases.…”