Clinical Validity and Utility of Genetic Testing in Common Multifactorial Diseases

Key Points

• All commercial providers of genetic tests for common multifactorial diseases (CMD), and most, if not all, large scale genetic epidemiological projects on CMD, claim a potential diagnostic impact of the currently available information on the respective disease-gene association.

• A genetic susceptibility test for a CMD may be useful in a public health context, i.e. trigger one or more preventive measures at an economically sensible level, if the (relative) risk of a sufficiently frequent genotype is sufficiently high and if carriers of that risk genotype benefit enough from the available preventions.

• The relative risks of genetic susceptibility factors for CMD must be quantified in large studies before their clinical utility can be valuated. Currently, such information is either scanty or discouraging. The vast majority of known relative genetic risks for CMD are smaller than 1.5 and are therefore unlikely to trigger preventive measures.

• The most promising candidates for CMD causation are mildly deleterious mutations, which are inherently likely to occur at sub-polymorphic frequency owing to selection. These variants will therefore be inefficient to screen for at a population-wide level.

• Information about interaction between genetic risk factors for CMD is a prerequisite for risk profiling, i.e. the joint assessment of multiple risk factors at a time, to be appropriate and advantageous. Currently, however, such information is lacking for most if not all CMD for which genetic tests are being offered.