P003 Clinical variability of the CFTR variant p.Arg117Cys uncovered by newborn screening for cystic fibrosis. Does the genetic background matter?

Objectives: The second most common CF-causing variant identified in the Norwegian newborn screening (NBS) is the CFTR variant p.Arg117Cys. Prior to CF screening, the variant was only found in 5% of clinically diagnosed CF patients. Methods: From 2012 until 2015, 500 samples per year were tested using Luminex CFTR 71 variant specific assay. After lowering the IRT cut-off value, 2500 samples per year were sequenced using MiSeq 139 Variants v1 (2015–2021) and CFTR Clinical Sequencing v2 (2021–2022). All samples with at least one allele p.Arg117Cys detected during the 11 years (2012–2022) of screening were selected. The p.Arg117Cys carrying samples from 2012–2015 were retrieved from the NBS biobank and re-tested with MiSeqDx Clinical Sequencing. Clinical follow-up data of the infants with screening positive results were available. Results: Among ~21,500 samples tested, 35 were NBS positive carrying at least one allele p.Arg117Cys, eight of them homozygous. There were 306 heterozygous carriers, which were defined as NBS negative. The frequency of p.Arg117Cys compared to the other pathogenic CFTR variants was 18–28%, and with a higher allele prevalence in the Norwegian population compared to publicly available databases. A variable clinical spectrum was uncovered among the NBS positives, even with identical pathogenic variant on the other allele. Co-occurring previously unevaluated CFTR variants were revealed in the whole gene sequenced samples. This extended allele background can be of importance and include disease modifying variants in CFTR. Conclusion: The knowledge of the landscape of CFTR variants changed and expanded with more extended sequencing of the gene. This additional allele background may be of importance and include disease modifying variants in CFTR.Future studies may explore how to predict the clinical variability of CFTR variants by combining whole CFTR sequencing and filtered whole genome sequencing.