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Three common CFTR mutations should be included in a neonatal screening programme for cystic fibrosis in Sweden
C Schaedel1, L Hjelte, I de Monestrol
1Department of Paediatrics, University Hospitals, Lund, Sweden. charlotta.schaedel@barn.lund.ltskane.se
Insights
Neonatal screening for cystic fibrosis (CF) improves outcomes. Adding two common CFTR mutations (394delTT, 3659delC) to screening protocols significantly reduces false negatives, improving early detection.
Area of Science:
- Medical Genetics
- Pediatric Medicine
- Screening Programs
Background:
- Neonatal screening for cystic fibrosis (CF) offers advantages in nutritional development.
- The immunoreactive trypsinogen (IRT)/DNA protocol is superior to single-tier IRT for screening accuracy.
- DNA testing requires population-specific mutation panels.
Purpose of the Study:
- To analyze CFTR mutations in Swedish CF patients.
- To evaluate the effectiveness of including additional mutations in neonatal screening.
- To develop a method for analyzing mutations from Guthrie cards.
Main Methods:
- Genotyping of 331 CF patients from Stockholm, Lund, and Uppsala.
- Analysis of CFTR gene mutations, focusing on deltaF508, 394delTT, and 3659delC.
- Development of a method for mutation analysis on Guthrie cards.
Main Results:
- The deltaF508 mutation frequency was 68.3% among CF alleles.
- Mutations 394delTT (8.5%) and 3659delC (7.9%) were frequent in the Swedish population.
- A combined panel of deltaF508, 394delTT, and 3659delC is expected to identify 97.6% of CF alleles.
Conclusions:
- Including 394delTT and 3659delC in CF screening protocols enhances detection rates.
- A simplified analysis method for Guthrie cards has been established.
- Optimized screening protocols can significantly reduce false-negative outcomes in cystic fibrosis diagnosis.
Abstract:
Children with cystic fibrosis (CF) diagnosed by neonatal screening have a better nutritional development and other advantages compared with those in a nonscreened group. The two-tier immunoreactive trypsinogen (IRT)/DNA screening protocol has been found superior to the single-tier IRT approach, improving the positive predictive value and thus reducing the false-positive rate. However, variations of the DNA test are required for different populations. In this study we examined CFTR (cystic fibrosis transmembrane conductance regulator) mutations in 331 CF patients attending the centres in Stockholm, Lund and Uppsala, comprising about 75% of the CF population in Sweden. The frequency of deltaF508 among CF alleles was 68.3%. There were two other mutations, 394delTT and 3659delC, found to be fairly frequent, amounting to 8.5 and 7.9%, respectively. Other mutations were comparatively rare. A simple and effective method of analysing the three mutations from Guthrie cards has been developed. Assuming Hardy-Weinberg equilibrium, 90% of our CF patients will be expected to carry at least one deltaF508 allele and 97.6% to carry at least one deltaF508, 394delTT or 3659delC copy. Including the latter two in a screening programme would thus substantially reduce the risk of a false-negative outcome.