Mutation characterisation of the cystic fibrosis transmembrane conductance regulator (CFTR) gene in people with cystic fibrosis in Northern Ireland.

Background: Cystic fibrosis (CF), which is caused by mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene is the most common life-limiting autosomal recessive genetic disease in Northern Ireland. Currently, Northern Ireland has approximately 520 people with CF (PwCF) (312 adults, 208 children) and a defective gene carrier rate of 1 in 22 persons, with approximately 86,507 carriers within the general population. Advances in DNA sequencing technology has allowed for better genetic characterisation of CFTR mutations. The aim of this project was to (i) examine current CFTR mutation frequency and type in paediatric and adult CF populations in Northern Ireland, (ii) examine CFTR mutational trends in relation to CF patients' age groups, (iii) compare Northern Ireland CFTR most common allele frequencies with those documented globally and (iv) establish a reference/baseline of CFTR mutation information prior to the effect of CFTR modulator therapy. Methods: Anonymised data comprising of birth year, sex, and known alleles of adult and paediatric individuals (n=520) from the Northern Ireland CF population was examined. Alleles were recorded according to legacy, protein and cDNA name and organised by mutation class and type, in accordance with CFTR2 database nomenclature. Individual known alleles frequencies from the complete Northern Ireland CF population (n=1005) were calculated and compared with the CFTR2 database, globally with CFTR data obtained from CF national registries. Results: Within the Northern Ireland CF population, there were 61 different CFTR mutational variants identified in a population of 1005 alleles. In descending occurrence, the most common was F508del with 626 alleles (62.3%), followed by R117H (8.9%), G551D (5.0%), G542X (3.3%), R560T (2.8%) and P67L (2.2%). The remaining alleles were present at a frequency of <2.0%. The six most frequently detected CFTR mutations accounted for 84.4% of all alleles. Over approximately two and a half decades (1996-2021), 23 CFTR mutations remain shared. Six alleles, which were described in the 1996 CFTR analysis, were absent from the 2021 data, whilst there were additional descriptions of 39 allelic mutations, which occurred in the 2021 analysis, but which were not described in the 1996 analysis. Conclusion: Characterisation of CFTR mutation alleles from people with cystic fibrosis provides essential information to help predict disease severity and effect of targeted CFTR modulator therapy. These 2021 data provide a valuable genetic update from the 1996 data and a reference point on the status of the Northern Ireland CFTR mutation types and frequencies. CFTR modulator therapy has the potential to indirectly alter the current