Background: Cystic fibrosis newborn screening is now implemented universally in France, as well as in many states in the United States and in various areas of Europe and Australia. Because the screening protocol usually includes the analysis of the most common CFTR mutations, it is of the utmost importance that only mutations that result in classical cystic fibrosis are included in this test. The panels of mutations used in most cystic fibrosis newborn screening programs enable the detection of a relatively frequent CFTR variant (R117H) whose implication in cystic fibrosis remains unclear. Physicians, therefore, have difficulty managing detected compound heterozygotes with this variant, which raises the issue of the appropriateness of extended testing in families and of the legitimate use of prenatal diagnosis.
Objective: The aim of this study was to describe the clinical outcome of the children found to be compound heterozygous for R117H by screening in Brittany (western France), where cystic fibrosis newborn screening was set up in 1989, and to assess whether this CFTR variant should be included in the newborn screening mutation panels.
Methods: Data on clinical status were obtained by the referring pediatricians.
Results: Since our screening protocol has enabled detection of R117H (ie, in 1995), 360466 newborns have been screened for cystic fibrosis in Brittany, of whom 124 had elevated immunoreactive trypsin and 2 mutations in the CFTR gene. Nine of these children (7.3%) were compound heterozygous for R117H, which in all cases was linked to the 7T_11TG haplotype [IVS8-nT variant/m(TG) repeat]. Their genotypes were F508del/R117H (n = 7), I507del/R117H (n = 1), or G551D/R117H (n = 1). At the time of this writing, the mean age of these 9 children was 7.0 years (the oldest being >10 years of age), and none of them had yet developed any signs of cystic fibrosis; they have been pancreatic sufficient and have had good nutritional status and pulmonary function. Moreover, we observed that, in Brittany, all the patients carrying the R117H variant have been identified exclusively through cystic fibrosis newborn screening.
Conclusions: In view of the high frequency of R117H-7T identified by cystic fibrosis newborn screening, the uncertain outcome of the asymptomatic children, and physicians' difficulty in managing these situations, we propose the withdrawal of the R117H variant from the panels of CFTR mutations used in cystic fibrosis newborn screening, given the expanding implementation of cystic fibrosis newborn screening.