Cystic fibrosis newborn screening in Denmark: Experience from the first 2 years

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.