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Mutation and haplotype analysis of the CFTR gene in atypically mild cystic fibrosis patients from Northern Ireland

Editor—Although cystic fibrosis (CF) is a monogenic disorder of autosomal recessive inheritance, it displays a diverse clinical phenotype. Over 1000 molecular lesions in the cystic fibrosis transmembrane conductance regulator ( CFTR ) gene together with the action of modifying genes can result in the variable expression of CF.1 2 

Classical CF causes dysfunction of the lung, sweat glands, testis, ovary, intestine, and pancreas.3 However, there is considerable variation in measurements of the onset age, presence of pancreatic insufficiency, sweat electrolyte levels, and progression of lung disease. Particularly mild manifestations of cystic fibrosis are conveniently grouped as “atypical CF” and result from a different CFTR mutation spectrum from classical CF patients.4-8 Recognition of the wide range of disease presentation in CF is important for appropriate treatment and effective counselling of those at risk. The repertoire of other disorders associated with CFTR variants include various respiratory afflictions such as asthma,9 chronic bronchitis, disseminated bronchiectasis,6 7 10 allergic bronchopulmonary aspergillosis,11 nasal polyposis,12 chronic pancreatitis,13 and certain forms of male infertility characterised as congenital absence of the vas deferens (CAVD) and obstructive azoospermia.8 14 

This report details the CFTR variants, characterised by fluorescent sequencing after screening the entire coding and surrounding intronic sequences by denaturing gradient gel electrophoresis (DGGE), in a panel of 31 unrelated atypical CF patients from Northern Ireland. The frequencies of these variants in the normal population was also examined. Automated detection of fluorescently labelled multiplex PCR fragments was used to type three intragenic CFTR dinucleotide repeats for assigning microsatellite haplotypes to the atypical CF alleles.15The genotypes for a functionally important polythymidine branch/acceptor site of intron 8 in the CFTR gene (Tn=IVS8-6(T)n)16 were also typed for our CF, atypical CF, and normal chromosomes.

The affected subjects from Northern Ireland …