More than 2000 CFTR pathogenic mutations have been reported in patients with Cystic Fibrosis (CF) and CFTR-related disorders (CFTR-RD) and explains to some extent the clinical heterogeneity of the disease. The pathogenic mutation p.Cys1400Ter is one of the rare CFTR mutations described in Cyprus. We aimed to define the prevalence and the origin of this mutation in the local population.

For the genotypic analysis of the CFTR gene we used the Devyser CFTR NGS kit on an Illumina MiSeq platform using a 150 bp paired-end reads with a minimum coverage of 150X. The Amplicon Suite software was used to read alignment and variant calling. For the haplotype analysis we performed multiplex PCR using five STR markers flanking the CFTR gene analysed by capillary electrophoresis on an ABI 3500xl genetic analyser.

We identified the p.Cys1400Ter mutation in 17 subjects, including 6 probands from 6 non-related Cypriot families. Three of these are diagnosed with CF, presenting with a second CF-causing mutation and typical CF symptoms. Two are diagnosed with CFTR-RD, presenting with bronchiectasis, intermediate sweat test and a second mutation. Three other carriers without a second mutation have a high suspicion of CFTR-RD, with bronchiectasis and intermediate sweat test (Castellani et al, 2022). All carriers share a common haplotype. For all of them the p.Cys1400Ter mutation co-segregates with the intronic variant c.489+3A>G in the same allele.

We speculate that p.Cys1400Ter co-segregated with c.489+3A>G is an ancestral variant combination which possibly spread in Cyprus due to a founder effect. Because of its prevalence, it now belongs to the regular testing panel of CFTR mutations in the island of Cyprus.