The application of genetic analysis in cystic fibrosis.
Cystic fibrosis (CF) is the most common lethal autosomal recessive disease in
Caucasians, with an incidence of approximately 1 in 2,500 newborns and a carrier
frequency of 1 in 25. The major symptoms of the disease are due to malfunction of
exocrine glands; sweat glands in the skin secrete excessive sodium and chloride,
pancreatic ducts become blocked with thickened mucus, giving rise to pancreatic
insufficiency, and the lungs also produce a thickened mucus which facilitates
bacterial infection, notably with Pseudomonas species.
The gene for CF has been isolated and its product, Cystic Fibrosis Transmembrane
conductance Regulator (CFTR), has been determined. Over 240 different mutations
of the CFTR gene have so far been described, and most of these have been shown
to be disease-causing.
CFTR protein is itself a chloride channel regulated by cyclic AMP-dependent
protein kinase and it is expressed primarily in epithelial cells. The highest level of
transcription is found in those tissues involved in the major symptoms of the disease,
notably the pancreas, sweat and salivary glands, the intestine and the reproductive
Genetic analysis in cystic fibrosis has enabled accurate first-trimester prenatal
diagnosis, initially using linked markers and latterly using direct mutation analysis.
Since the isolation of the gene in 1989 it has become of considerable importance to
identify CF mutations in a population (for the purpose of population screening) and
in individuals with CF (to enable carrier detection and prenatal diagnosis within
that family). To that end, the CF population of the North-West of England has been
extensively studied. A total of 1108 CF chromosomes of the native North-West
population have been investigated and 92% of mutations (comprising 20 different
mutations of the CFTR gene) in that group have been identified.
Two further groups were of interest, namely a small number of Pakistani CF
patients in whom 50% of mutations were identified, and a phenotypically variant
group with atypical sweat test results, which yielded no mutations.
During the course of the investigation, five previously unrecorded mutations were identified: DeltaI507 in a patient from Bath, 300delA in one from Birmingham,
1161de1C in a Pakistani CF patient, and E60X and 1138insG in patients from the
North-West of England. Since these comprise a three-base deletion, a stop codon
mutation, and three frameshift mutations, they can all be accepted as diseasecausing
While some headway has been made in identifying CF mutations in Pakistani
patients, none has been possible in the phenotypically variant group. There remains
some doubt, therefore, that individuals in the latter group do in fact have CF or
whether a phenocopy disease is present.