ANALYSIS OF EXTRA- AND INTRAGENIC MARKER HAPLOTYPES AS PART OF MOLECULAR DIAGNOSIS OF CYSTIC FIBROSIS IN PATIENTS FROM SERBIA

Abstract — Cystic fibrosis (CF) is the most common fatal autosomal recessive disease in Caucasians. Since characterization of F508del, the predominant mutation in different countries, more than 1500 mutations have been discovered in the CFTR gene, including a large number of polymorphisms. After molecular screening of 222 CF patients from Serbia, we detected 21 different CFTR mutations, F508del being the most frequent (69.59 % of CF alleles). A total of 21 mutations cover almost 80 % of CF alleles in this group. Since the molecular basis of CF is highly heterogeneous in our population, studying thye haplotype association with normal and CF chromosomes could be very helpful in all cases where one or both mutations remain unidentified. Haplotype analysis was done using six diallelic sites and one tetranucleotide repeat (XV2C-KM19-MP6D9-J44-IVS6a(GATT)-M470V-T854T) on 99 F508del, 90 non-F508del, and 105 normal chromosomes. Strong linkage disequilibrium was observed for CFTR mutations and one haplotype (1-2-2-1-6(2)-1-1), while normal chromosomes were mostly associated with another (1-1-2-1-6(2)-1-2). The obtained results show that in most cases it would be possible with this group of polymorphisms to separate normal chromosomes from chromosomes which carry the CFTR mutation. As far as prenatal diagnosis of cystic fibrosis is concerned, haplotype analysis can be used as a helpful method of indirect diagnosis in families at risk with one or both CF alleles uncharacterized