Molecular Genetics

The technical challenge of CF mutation detection derives from the large size of the gene, the myriad possible mutations, and the lack of any mutational ''hotspots'' in the gene, which could be used to limit the necessary targets for analysis. The core panel of 25 mutations designated for population screening in the United States was chosen on the basis of their prevalence (>0.1%) among a large cohort of genotyped affecteds, rather than their convenient location within the gene (on the contrary, they are spread throughout its length).

As more patients and mutations have been studied, the range and complexity of the molecular genetics have continued to grow. For example, some male individuals with CFTR mutations may present only with CBAVD and no classical CF symptoms, being ascertained during workups for infertility. Furthermore, one of the more common mutations, R117H, may be associated with either CF or CBAVD, depending on which form of an intronic repeat polymorphism it is coupled with. When R117H is on the same chromosome (in cis) with a run of 5 thymidines (5T) in intron 8 of the gene, it behaves as a CF mutation (albeit usually mild); when in cis with the 7T allele it becomes a CBAVD mutation.

An analogous situation has emerged for one of the other mutations in the core panel, I148T, but not until after widespread screening had commenced. Reports from large testing laboratories1-8,9-1 indicated that this mutation was seen in carriers at almost 100 times the expected frequency based on its appearance in affected patients. Rohlfs et al.[8] identified a genetic modifier, a deletion of 6 base pairs, 3199del6, which was an obligate covariant for I148T to behave as a disease-causing allele. In retrospect, these findings are not surprising, as the clinical variability of CF patients with the same primary mutations must be due to the presence of genetic modifiers, both within the CFTR gene and elsewhere in the genome, of which we still know all too little.

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