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By performing extensive scanning of whole coding and flanking sequences of the cystic fibrosis (CF) transmembrane conductance regulator (CFTR) gene, we had previously identified the CF-causing mutations in black South African patients of different ethnic groups suspected with the disease. Of ten samples analyzed, there were six remaining that had either one (n = 2) or two (n = 4) unidentified CFTR alleles that have now been tested for large rearrangements using a semiquantitative fluorescent PCR assay. A novel deletion encompassing CFTR exon 2 was detected in one patient who was heterozygous for the mutation 3120+1G>A. The Caucasian deletion involving the same exon [c.54-5811_c.164+2186del8108ins182] was ruled out. The DNA had been stored for more than 12 years and only minute quantities remained. We thus used a whole-genome amplification method based on multiple displacement amplification to generate sufficient amounts of DNA to characterize the intronic breakpoints and identify the deletion at the genomic level. Mapping and sequencing the breakpoint junctions revealed a novel large deletion [c.54-1161_c.164+1603del2875]. We have designed a simple test to specifically detect the presence or absence of this large rearrangement. This study reports the first large CFTR rearrangement in a black South African CF patient, further defining the molecular spectrum of CF that will be useful for improving genetic testing and counseling in this region.

The spectrum of CFTR mutations in three South African populations is presented. To date. a total of 192 white patients (384 chromosomes) with confirmed CF have been tested. deltaF508 accounts for 76% of the CF chromosomes in this group, with 3272-26A-->G, 394delTT and G542X occurring at the following frequencies: 4, 3.6 and 1.3%, respectively. A further 11 mutations account for 6% of CF chromosomes. A total of 91% of the CF-causing mutations can now be detected in the South African white population. Haplotype analysis suggests a founder effect in South Africans of European origin for the two common CFTR mutations, 3272-26A-->G and 394delTT. The diagnosis of CF has been confirmed in 14 coloured and 12 black CF patients. In the coloured population, both the deltaF508 and 3120 + 1G-->A mutations occur at appreciable frequencies of 43 and 29%, respectively. In the black population, the most common CF-causing mutation, the 3120 + 1G-->A mutation, occurs at an estimated frequency of 46%. Four other mutations have been detected, resulting in the identification of a total of 62.5% of mutations in this population.

Cystic fibrosis (CF) is thought to be rare in the black populations of Africa who have minimal white admixture. Only a few cases have been reported but have not been studied at the molecular level. We report the detection of CFTR mutations in three southern African black patients. One was homozygous for the 3120 + 1G-->A mutation, while the other two were compound heterozygotes each with this mutation on one chromosome. The other mutations were G1249E and a previously unreported in frame 54 bp deletion within exon 17a involving nucleotides 3196-3249 (3196del54). The 3120 + 1G-->A mutation was first described in American black patients and has been shown to be a common mutation in this population (9-14% of CF chromosomes). It was also found in a black CF patient whose father, the 3120 + 1G-->A carrier, is from Cameroon. These data suggest that it is an old mutation which accounts for many of the CFTR mutations in African blacks.