Marianne Skov1, Marie Baekvad-Hansen2, David M Hougaard2, Kristin Skogstrand2, Allan M Lund3, Tania Pressler1, Hanne V Olesen4, Morten Duno5. 1. Department of Pediatrics, CF Center Copenhagen, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 2. Department for Congenital Disorders, Center for Neonatal Screening, Statens Serum Institut, Copenhagen, Denmark. 3. Departments of Pediatrics and Clinical Genetics, Center for Inherited Metabolic Diseases, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark. 4. Department of Pediatrics, CF Center Aarhus, Aarhus University Hospital, Aarhus, Denmark. 5. Department of Clinical Genetics, Molecular Genetics Laboratory, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Abstract
BACKGROUND: In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented. METHODS: The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed. RESULTS: Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF. CONCLUSIONS: During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.
BACKGROUND: In Denmark, newborn screening (NBS) for cystic fibrosis (CF) was introduced on 1 May 2016. The implementation and results from the first 2 years of the national newborn CF screening program are presented. METHODS: The screening included immunoreactive trypsinogen (IRT), followed by evaluation for the F508del mutation when a value at or above the 50 ng/mL cutoff was present. In cases with a single F508del mutation or a very high IRT value above 145 ng/mL, next-generation sequencing of the CF transmembrane conductance regulator gene (CFTR) was performed. RESULTS: Of 126 522 newborn infants 126 338 were tested (99.85%), and 4730 samples (3.7%) were assessed for CFTR mutations. Twenty-six infants were screen-positive and referred for diagnostic follow-up of whom 22 were confirmed to have a CF diagnosis, four had one known and one CFTR allele with unknown pathogenicity, classified as cystic fibrosis screening positive inconclusive diagnosis (CFSPID), PPV 84.6%. One of the four children classified as CFSPID was later found to carry the two identified CFTR variants in cis and was reclassified as a carrier of CF. We found two false negatives; one exhibited an IRT level above the 50 ng/mL cutoff but was below the 145 ng/mL very high cutoff and with no F508del mutation present. The second false-negative fell below the 50 ng/mL IRT cutoff but was diagnosed shortly after birth on the basis of meconium ileus. Screening sensitivity, 91.7%. Two hundred thirty-two children were identified as carriers of CF, which is twofold above the estimated annual number of carriers. All but one carrier were heterozygous for the F508del CFTR mutation. Sixteen percent of the sequenced samples revealed rare CFTR variants, which were classified as nonpathogenic in relation to CF. CONCLUSIONS: During the first 2 years of NBS CF screening in Denmark, we identified close to the expected number of infants with CF using an algorithm based on IRT, presence of F508del mutation and comprehensive genetic analysis. CFSPID accounted for only a small minority, despite comprehensive CFTR sequencing, whereas more carriers than initially expected were identified.
Authors: Maximilian Zeyda; Andrea Schanzer; Pavel Basek; Vera Bauer; Ernst Eber; Helmut Ellemunter; Margit Kallinger; Josef Riedler; Christina Thir; Franz Wadlegger; Angela Zacharasiewicz; Sabine Renner Journal: Diagnostics (Basel) Date: 2021-02-13
Authors: Cecilia Catellani; Francesca Cirillo; Sara Graziano; Luisa Montanini; Nelson Marmiroli; Mariolina Gullì; Maria Elisabeth Street Journal: Acta Biomed Date: 2022-07-01