Mutation analyses have only three possible results: (1) no mutation detected, the patient is normal at a specific allele; (2) one mutation detected, the patient is heterozygous or a carrier of the mutation; or (3) two mutations detected, the patient is homozygous or genetically affected. However, reporting of CF results is more complex because not all CFTR mutations are tested for and different interpretations for each of the possible results exists depending on the indication for the test and the ethnicity and family history of the consultand.
For example, in a screening program, the finding of one mutation in an asymptomatic patient demonstrates that the patient is a carrier but has a very different interpretation in a diagnostic context. For a symptomatic patient, detection of one mutation could mean that the patient is indeed a CF carrier; however, a second possibility is that the patient might also be a compound heterozygote for one identified mutation and a second, unidentified mutation that is either private or rare. In a diagnostic setting, the finding of two mutations confirms a diagnosis of CF. However, genotype-phenotype relationships are not well enough established that prognostic statements can be made for the many different possible homozygous and compound heterozygous genotypes. The interpretation of one or no detected mutations for a symptomatic patient must include a recommendation for diagnostic sweat electrolyte analysis.
Most CF testing referrals are for carrier screening. Although the finding of one mutation in this context is straightforward, the majority of these analysis are negative—no mutations detected. In these cases, the physician must be informed that the revised carrier risk, although reduced from the prior risk, is a nonzero number because detection is incomplete (i.e., not all mutations tested for). Prior and revised carrier risks are both dependent on patient ethnicity and family history. Prior carrier risks for patients with a negative family history are calculated from the ethnic frequency of CF. Prior carrier risks for patients with a positive family history are based on pedigree analysis. Thus, responsible reporting for CF mutation analysis incorporates the indication for the test, patient ethnicity, and family history. Model laboratory reports can be found in the published ACMG/ACOG recommendations for detection of no or one mutation in a carrier context for individuals with a negative personal and family history (56).
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