Genotype and phenotype

A person’s genotype is their unique sequence of DNA. More specifically, this term is used to refer to the two alleles a person has inherited for a particular gene. Phenotype is the detectable expression of this genotype – a patient’s clinical presentation. A person’s phenotype results from the interaction between their genotype and their environment.

The connection between genotype and phenotype is not always clear-cut. This means that you may encounter disparities between your patient’s genomic test result and their clinical presentation. Similarly, the phenotype of patients with a given genetic condition may vary greatly even within families. Reasons for this disparity include:

Reduced penetrance

Penetrance refers to the proportion of people carrying a particular variant who express the associated condition.

Some conditions are associated with 100% penetrance, or complete penetrance. This means that every person who has the causative genetic variant will develop symptoms of the condition within their lifetime.

Examples: neurofibromatosis type 1, Huntington disease.

When this proportion is less than 100%, the conditions is said to have reduced penetrance. The reason for reduced penetrance is likely a combination of genetic, environmental and lifestyle factors, many of which are not yet well understood. For example, many familial cancer syndromes have reduced penetrance, which can make it difficult to accurately predict the risk of family members developing these conditions.

Variable expressivity

This refers to the range of phenotypes occurring in patients with the same genetic condition. A patient with a particular variant may have mild symptoms, while another patient with the same variant has severe disease. As with reduced penetrance, the reasons for variable expressivity are not well understood. If a genetic condition has highly variable symptoms, it may be more challenging to diagnose. Variable expressivity is common in both dominant and recessive conditions.

Examples: Lynch syndrome previously known as hereditary non-polyposis colorectal cancer (HNPCC), Charcot-Marie-Tooth disease