Screening for Mendelian or orphan hereditary diseases only makes it possible to explain a very small part of an individual disease.

In fact, mutations are extremely rare in the general population (BMC Med Genomics 2015; 8:37).

Consequently, to enable the greatest possible number of patients to benefit from genomic medicine (e.g. in terms of risk reduction measures for people exposed to a very high risk, or general preventive measures, such as physical activity and diet, and special monitoring of complications), other tools have been developed. The key tool is the polygenic risk score (PRS). This is based on the fact that hundreds, if not thousands, of genetic variants present in everybody, known as SNPs (single nucleotide polymorphisms), individually exert a very weak effect on any given disease. However, if their combined effect is calculated, this will be just as significant as that caused by a mutation, whereas a much larger number of people will be concerned compared to a mutation (see graph).

By way of example, we will now discuss the clinical application of PRS for coronary heart disease (taken from Nat Rev Genet 2018; 19:581-590).

The left-hand panel of the graph, in red, shows clinical risk factors and their frequency in the population.
The PRS is in the centre, in blue, defining a person’s individual genetic risk of developing the disease (high risk is between the 80th and 100th percentile).
On the right, the practical application of the concept is shown; this stipulates that the clinical and genetic risk determined by PRS are used together to define a risk threshold, above which therapeutic management will be necessary and beneficial (e.g. drug-induced reduction of cholesterol, a therapeutic decrease in blood pressure, weight loss, increased physical activity, etc.). Note that the combination of the two risks makes it possible specifically to discern those individuals exposed to clinical risk, who at the same time are also at high genetic risk, and who benefit the most from these measures.

Screening for Mendelian or orphan hereditary diseases at Genesupport