Genetic testing allows us to detect discrete genetic variants for diseases and traits, and yet in real life, the manifestations sometimes appear more like shades of gray than black and white. If a pet has a genetic variant detected, shouldn’t that mean that the clinical result is a foregone conclusion? Like much of medicine the answer is both yes and no. Here’s why.
To understand the situation, we need to go back to a basic tenet of genetics – genetic mutations/variants don’t cause disease – they code for proteins that may not be fully functional and it is this dysfunction that is interpreted as disease. The body tends to have a lot of redundant systems, so there may be other genes, epigenetic markers, modifiers, suppressors and environmental factors that all impact the clinical manifestations in the living patient.
Clinical diagnosis also requires that we be able to clinically differentiate between the “normal” gene and the “variant” gene in all cases within a population of animals, and this is referred to as penetrance. Penetrance can be defined as the percentage of individuals in a population with a given genetic variant (genotype) that fully display the clinical manifestations (phenotype), and this is rarely 100%. Because of this, many conditions are described as having incomplete penetrance and this explains why we can’t fully predict the clinical situation, even with sophisticated genetic screening. Some disorders may have full (100%) penetrance, but many more do not.
In contradistinction to penetrance, which looks at genetic manifestations on a population level, expressivity measures the extent to which a genetic variant (genotype) actually expresses the so-called clinical abnormality (phenotype) on an individual level. There can be different degrees of expression of identical variants in different individuals based on other genes present or environmental factors. Because of this, we might describe that there could be variable expressivity for this variant in different individuals.
These features of penetrance and expressivity make genetic counseling as much an art as a science, even given the certainty of genetic screening. It is also a great reason why genetic testing favors the nuanced interpretation by well-trained veterinary teams to properly counsel pet owners on the benefits of personalized medicine and the goal of helping pets live long, healthy and happy lives.
This article was written by Lowell Ackerman DVM DACVD MBA MPA CVA MRCVS, and originally appeared in Orivet’s December 2017 Newsletter