Abstract
Background: Cystic fibrosis (CF) is one of the most common life-threatening genetic disorders. Around 2000 variants in the CFTR gene have been identified, with some proportion known to be pathogenic and 300 disease-causing mutations have been characterized in detail by CFTR2 database, which complicates its analysis with conventional methods. Methods: We conducted next-generation sequencing (NGS) in a cohort of 89 adult patients negative for p.Phe508del homozygosity. Complete clinical and demographic information were available for 84 patients. Results: By combining MLPA with NGS, we identified disease-causing alleles in all the CF patients. Importantly, in 10% of cases, standard bioinformatics pipelines were inefficient in identifying causative mutations. Class IV-V mutations were observed in 38 (45%) cases, predominantly ones with pancreatic sufficient CF disease; rest of the patients had Class I-III mutations. Diabetes was seen only in patients homozygous for class I-III mutations. We found that 12% of the patients were heterozygous for more than two pathogenic CFTR mutations. Two patients were observed with p.[Arg1070Gln, Ser466] complex allele which was associated with milder pulmonary obstructions (FVC 107 and 109% versus 67%, CI 95%: 63-72%; FEV 90 and 111% versus 47%, CI 95%: 37-48%). For the first time p.[Phe508del, Leu467Phe] complex allele was reported, observed in four patients (5%). Conclusion: NGS can be a more information-gaining technology compared to standard methods. Combined with its equivalent diagnostic performance, it can therefore be implemented in the clinical practice, although careful validation is still required.
Original language | English |
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Article number | 13 |
Pages (from-to) | 13 |
Number of pages | 12 |
Journal | BMC Medical Genomics |
Volume | 11 |
Issue number | Suppl 1 |
DOIs | |
Publication status | Published - 13 Feb 2018 |
Keywords
- CFTR cystic fibrosis
- NGS next generation sequencing
- Cystic Fibrosis Transmembrane Conductance Regulator/deficiency
- Genetic Association Studies
- Biomarkers/analysis
- Humans
- Middle Aged
- Male
- High-Throughput Nucleotide Sequencing/methods
- Young Adult
- Adult
- Female
- Mutation
- Cystic Fibrosis/genetics
- Cohort Studies
- POPULATION
- VARIANTS
- CFTR GENE
- MISSENSE MUTATIONS
- ORIGIN
- SERVER
- DISEASE
- SPECTRUM
- CONDUCTANCE REGULATOR GENE