Association between haplotypes and specific mutations in Swiss cystic fibrosis families

Cystic fibrosis (CF) is the most common severe autosomal recessive genetic disorder in Caucasian populations, with an incidence of about 1 in 2000 live births, implying a carrier frequency of about 1 in 22. In 1989, the CF gene was isolated and characterized and the major mutation (delta F508), a 3-bp deletion that results in the loss of a phenylalanine residue at position 508, was detected. To determine the frequency of the delta F508 mutation and the predicted number of additional mutations in our population, we have undertaken a collaborative study of 215 CF patients and 175 CF parents in Switzerland. The delta F508 mutation in exon 10 has been found in 70% of the CF chromosomes, and the exon-11 mutation R553X seems to be the second most common CF mutation in our population, with a frequency of 5.3%, whereas the G551D mutation (also in exon 11) has not been detected at all. Haplotype determination of 430 CF and 175 normal chromosomes using XV-2c, KM19, MP6d-9, and J3.11 has been proven to be very helpful in providing additional carrier risk calculations: Haplotypes 1 (1221), 2 (1222), 6 (2111), and 7 (2221) increase the risk of being a carrier from 1 in 55 (haplotype 6) to 1 in 17 (haplotype 1), whereas haplotypes 3 (1122), 4 (1112), 8 (2222) and 10 (1111) lower the risk from 1 in 144 (haplotype 3) to 1 in 1678 (haplotype 10). Moreover, the mutation R553X shows strong correlation with haplotype 3, leading to the suggestion that haplotypes 1, 2, 5, and 6 may account for four additional mutations in Switzerland.(ABSTRACT TRUNCATED AT 250 WORDS)