Characterization of a novel 21-kb deletion, CFTRdele2,3(21 kb), in the CFTR gene: a cystic fibrosis mutation of Slavic origin common in Central and East Europe

We report a large genomic deletion of the cystic fibrosis transmembrane con ductance regulator (CFTR) gene, viz.. a deletion that is frequently observe d in Central and Eastern Europe. The mutation, termed CFTRdele2.3(21 kb), d eletes 21,080 bp spanning introns 1-3 of the CFTR gene. Transcript analyses have revealed that this deletion results in the loss of exons 2 and 3 in e pithelial CFTR mRNA, thereby producing a premature termination signal withi n exon 4. In order to develop a simple polymerase chain reaction assay for this allele, we defined the end-points of the deletion at the DNA sequence level. We next screened for this mutation in a representative set of Europe an and European-derived populations. Some 197 CF patients, including seven homozygotes, bearing this mutation have been identified during the course o f our study. Clinical evaluation of CFTRdele2.3(21 kb) homozygotes and a co mparison of compound heterozygotes for Delta F508/CFTRdele2,3(21 kb) with p airwise-matched Delta F508 homozygotes indicate that this deletion represen ts a severe mutation associated with pancreatic insufficiency and early age at diagnosis. Current data show that the mutation is particularly common i n Czech (6.4% of all CF chromosomes), Russian (5.2%), Belorussian (3.3%). A ustrian (2.6%), German (1.5%), Polish (1.5%), Slovenian (1.5%), Ukrainian ( 1.2%), and Slovak patients (1.1%). It has also been found in Lithuania, Lat via, Macedonia and Greece and has sporadically been observed in Canada, USA , France, Spain, Turkey, and UK, but not in CF patients from Bulgaria, Croa tia, Romania or Serbia. Haplotype analysis has identified the same extragen ic CF-haplotype: XV-2c/KM. 19 "A" and the same infrequent intragenic micros atellite haplotype 16-33-13 (IVS8CA-IVS17bTA-IVSI7bCA) in all examined CFTR dele2,3(21 kb) chromosomes, suggesting a common origin for this deletion. W e conclude that the 21-kb deletion is a frequent and severe CF mutation in populations of Eastern- and Western-Slavic descent.